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Compendium on the Pathophysiology and

Treatment of Hypertension
Preeclampsia
Pathophysiology, Challenges, and Perspectives
Sarosh Rana, Elizabeth Lemoine, Joey Granger, S. Ananth Karumanchi

Abstract: Hypertensive disorders of pregnancy—chronic hypertension, gestational hypertension, and preeclampsia—


are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and
fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most
feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third
trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus.
While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central
to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal
placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine
kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker
assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic
pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and
children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for
an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular
disease in women.   (Circ Res. 2019;124:1094-1112. DOI: 10.1161/CIRCRESAHA.118.313276.)
Key Words: biomarkers ◼ blood pressure ◼ cardiovascular disease ◼ preeclampsia ◼ pregnancy

H ypertensive disorders are a common complication of


pregnancy that put women and their fetuses at dispro-
important risk factor for peripartum morbidity in the United
States.6 Hypertensive disorders of pregnancy and in particu-
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portionate risk for further complications, as well as life-long lar preterm preeclampsia is also associated with substantial
sequelae. Ranging in severity, hypertensive disorders of preg- risk for cardiovascular disease (CVD) and cerebrovascular
nancy include chronic hypertension—systolic blood pressure disease in the long-term.7,8
(BP) ≥140 mm Hg or diastolic BP ≥90 mm Hg that predates
the onset of pregnancy; gestational hypertension—hyperten- Epidemiology and Clinical Definition
sion diagnosed after 20 weeks gestation without concurrent of Preeclampsia
proteinuria; preeclampsia-eclampsia—classically, new-onset Risk Factors for Preeclampsia
hypertension with new-onset proteinuria; and chronic hyper- Risk factors for the development of preeclampsia have been
tension with superimposed preeclampsia—chronic hyperten- studied extensively (Table 1). Major risk factors include a
sion with new-onset proteinuria or other signs/symptoms of history of preeclampsia, chronic hypertension, pregesta-
preeclampsia after 20 weeks or chronic proteinuria with new- tional diabetes mellitus, antiphospholipid syndrome, and o-
onset hypertension.1 With the greatest morbidity and mortality, besity, among others.9 Other risk factors include advanced
preeclampsia affects 5% to 7% of all pregnant women but is maternal age, nulliparity, history of chronic kidney disease,
responsible for over 70 000 maternal deaths and 500 000 fetal and use of assisted reproductive technologies. Relatively
deaths worldwide every year. In the United States, it is a leading rare risk factors are a family history of preeclampsia and
cause of maternal death, severe maternal morbidity, maternal mother carrying a trisomy 13 fetus.10,11 Genetic susceptibil-
intensive care admissions, cesarean section, and prematurity.2–4 ity to preeclampsia has been extensively studied.12,13 A 2017
Delivery can resolve most signs and symptoms; however, genome-wide association study analysis of neonates from
preeclampsia can persist after delivery and, in some cases, 4380 cases of preeclampsia and 310 238 controls found a
can develop de novo in the postpartum period.1,5 De novo genome-wide susceptibility locus (rs4769613; P=5.4×10−11)
or persistent postpartum preeclampsia has emerged as an near the FLT1 (FMS-like tyrosine kinase 1) gene, the protein

From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL (S.R.); Harvard Medical School,
Boston, MA (E.L.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.G.); Departments of Medicine, Obstetrics and
Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (S.A.K.); and Department of Medicine, Cedars-Sinai
Medical Center, Los Angeles, CA (E.L., S.A.K.).
Correspondence to S. Ananth Karumanchi, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90004. Email sananth.
karumanchi@csmc.edu
© 2019 American Heart Association, Inc.
Circulation Research is available at https://www.ahajournals.org/journal/res DOI: 10.1161/CIRCRESAHA.118.313276

1094
Rana et al   Preeclampsia and Vascular Disease   1095

Table 1.  Risk Factors for Preeclampsia


Nonstandard Abbreviations and Acronyms
Major Risk Factors
ACOG American College of Obstetrics and Gynecology
  Prior preeclampsia (RR, 8.4; 95% CI, 7.1–9.9)
Arrb1 β-arrestin-1
  Chronic hypertension (RR, 5.1; 95% CI, 4.0–6.5)
ASPRE aspirin for evidence-based preeclampsia preven-
tion trial   Pregestational diabetes mellitus (RR, 3.7; 95% CI, 3.1–4.3)
AT1-AA Angiotensin II type 1 receptor autoantibodies   Multiple gestation (RR, 2.9; 95% CI, 2.6–3.1)
AT1-B2 Angiotensin II type 1 receptor and Bradykinin B2
receptor complex   Prepregnancy BMI >30 (RR, 2.8; 95% CI, 2.6–3.1)
BP blood pressure   Antiphospholipid syndrome (RR, 2.8; 95% CI, 1.8–4.3)
COMT catechol-O-methyl transferase Other risk factors
CVD cardiovascular disease
  Systemic lupus erythematosus (RR, 2.5; 95% CI, 1.0–6.3)
DV decidual vasculopathy
ER endoplasmic reticulum   History of stillbirth (RR, 2.4; 95% CI, 1.7–3.4)
ET-1 endothelin-1   Prepregnancy BMI >25 (RR, 2.1; 95% CI, 2.0–2.2)
FLT1 fms-like tyrosine kinase   Nulliparity (RR, 2.1; 95% CI, 1.9–2.4)
HELLP syndrome Hemolysis Elevated Liver enzymes Low Platelets
syndrome   Prior placental abruption (RR, 2.0; 95% CI, 1.4–2.7)
HIF hypoxia-inducible factors   Assisted reproductive technology (RR, 1.8; 95% CI, 1.6–2.1)
HO heme oxygenase   Chronic kidney disease (RR, 1.8; 95% CI, 1.5–2.1)
hsFLT1 human soluble FMS-like tyrosine kinase 1
  Advanced maternal age >35 (RR, 1.2; 95% CI, 1.1–1.3)
KIR killer cell Ig-like receptors
IL interleukin   Genetic susceptibility (mother, father)
MHC major histocompatibility complex Rare risk factors
PAPP-A pregnancy-associated plasma protein A   Family history of preeclampsia
PGC-1a proangiogenic transcriptional cofactor- 1alpha
  Trisomy 13 fetus
PlGF placental growth factor
Relative Risk provided from meta-analyses by Ray et al.9 BMI indicates body
PPCM peripartum cardiomyopathy
mass index; and RR, relative risk.
PPV positive predictive value
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RNAi RNA interference technology Clinical Definition of Preeclampsia


ROS reactive oxygen species Classically, the American College of Obstetrics and
RR relative risk Gynecology (ACOG) defines preeclampsia as the presence
RUPP reduction in uterine perfusion pressure rodent model of hypertension and proteinuria occurring after 20 weeks of
sENG soluble endoglin gestation in a previously normotensive patient. However, a
sFLT1 soluble fms-like tyrosine kinase 1 significant proportion of women develop systemic manifesta-
SGA small for gestational age tions of preeclampsia—such as low platelets or elevated liver
StAmP Statins to ameliorate early onset preeclampsia trial enzymes—before the hallmark of proteinuria is detectable,16,17
STRIDER Sildenafil for severe fetal growth restriction trial resulting in delayed diagnoses. The evolving understanding
TF transcription factor of preeclampsia as a heterogeneous hypertensive disorder of
TGF-β1 transforming growth factor β1 pregnancy led to ACOG’s hypertension 2013 task force to re-
Th1/Th2 T helper type 1/type 2 cells vise the definition of preeclampsia to include the presence of
TNF Tumor necrosis factor severe features with or without proteinuria and to exclude de-
uNK uterine natural killer cell gree of proteinuria as a criterion of severe features (Table 2).1
UPR unfolded protein response These criteria were confirmed more recently in an update of
VEGF vascular endothelial growth factor
the ACOG’s practice guidelines.18

Pathogenesis of Preeclampsia
product of which is a well-established pathogenetic fac- A placental disease, preeclampsia progresses in 2 stages: (1) ab-
tor in preeclampsia.14 rs4769613 has a higher frequency in normal placentation early in the first trimester followed by (2) a
late-onset preeclampsia, exerts effects only in the fetal—not “maternal syndrome in the later second and third trimesters char-
maternal—genome, and has no difference in transmission acterized by an excess of antiangiogenic factors19,20 (Figure 1).
of disease association with parental sex inheritance, mak- While the mechanism of abnormal placentation is controversial,
ing the effects of imprinting unlikely. However, maternal animal models have demonstrated that uteroplacental ischemia
genetic susceptibility may play a role as well. A multieth- drives the hypertensive, multi-organ failure response observed
nic maternal preeclampsia genome-wide association study in the maternal preeclamptic syndrome21 (stage 2). A number of
discovered a genome-wide susceptibility locus at rs9478812 theories have been proposed for the placental dysfunction ob-
(P=5.90×10−7), an intronic region of protein PLEKHGI im- served in stage 1, including oxidative stress, abnormal natural
plicated in BP regulation.15 killer cells (NKs) at the maternal-fetal interface, and genetic and
1096  Circulation Research  March 29, 2019

Table 2.  Clinical Definition of Preeclampsia1 transformation of the spiral arteries, leading to placental ische-
Preeclampsia mia and the maternal syndrome of preeclampsia.25
Atherosclerotic changes in maternal radial arteries that
  Elevated blood pressure
supply the decidua—as opposed to the spiral arteries—are also
Systolic ≥140 mm Hg or diastolic ≥90 mm Hg, 2 occasions, 4 h apart
   observed in preeclampsia.30,31 Decidual vasculopathy (DV) is a
in previously normotensive woman lesion common to disorders of placental insufficiency, includ-
  AND Proteinuria ing intrauterine growth restriction and preeclampsia, and com-
  ≥300 mg/24 hour urine collection bines (1) acute atherotic lesions with (2) medial hypertrophy
and perivascular lymphocytes (Figure 2). Within preeclampsia
  or protein/creatinine ≥0.3
phenotypes, the presence of DV is associated with worse clin-
   or dipstick reading =1+ ical outcome, higher diastolic BP, worse renal function, and
  OR severe features* perinatal fetal death.32 Histologically, normal third-trimester
decidual vessels are characterized by flat endothelium and a
Severe features
loss of medial smooth muscle, while preeclamptic decidua
 Systolic blood pressure ≥160 mm Hg or diastolic ≥110 mm Hg, 2 show signs of loose, edematous endothelium, hypertrophy of
occasions, 4 h apart on bedrest
the vessel media, and loss of smooth muscle modifications (as
  Thrombocytopenia (<100 000 μL) seen in atherosclerosis), characterizing DV.30 Correlated with
 Liver function tests 2× normal or severe persistent right upper quadrant clinical diagnosis, DV has the highest association with pree-
or epigastric pain clampsia with small for gestational age (SGA) and a lesser but
 Serum creatinine concentration >1.1 mg/dL or doubling of creatinine in
significant association with SGA with doppler abnormalities,
the absence of other renal disease suggesting a pathogenetic similarity between SGA with dop-
pler abnormalities and preeclampsia with SGA at the level of
  Pulmonary edema
the decidua.30 Overall, there is significant evidence that decid-
  New-onset cerebral or visual symptoms ual vessels demonstrate secondary atherosclerotic changes in
preeclampsia. Further studies are needed to determine if these
changes are representative of the maternal systemic endothe-
environmental factors, though none have conclusive evidence in lial damage secondary to pathological changes such as hyper-
humans. However, substantive evidence supports the idea that tension or if DV contributes to the pathogenesis of stage 1.30
the diseased placenta leads to release of soluble toxic factors in In addition to uteroplacental insufficiency, epidemiological
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the maternal circulation that result in inflammation, endothelial studies suggest that poor uterine decidualization—the stromal
dysfunction, and maternal systemic disease.19,20,22 transformation of uterine endometrium to prepare for implan-
tation—may affect the development of preeclampsia. Global
Stage 1: Abnormal Placentation, Trophoblast transcriptional profiling of chorionic villus samples points to in-
Invasion, and the Maternal-Fetal Interface sufficient or defective decidualization in pregnancies that were
During normal placental implantation, cytotrophoblasts mi- later complicated by severe preeclampsia.33 Endometrial stromal
grate into the maternal uterine spiral arteries, forming vascular cells from nonpregnant donors with a history of severe preeclamp-
sinuses at the fetal-maternal interface to provide nutrition to sia fail to decidualize in vitro and are transcriptionally inert, sug-
the fetus. In normal pregnancy, this invasion progresses deeply gesting baseline genetic abnormalities or genetic modifications.34
into the spiral artery to the level of the myometrium,23,24 which Finally, global transcriptional profiling of decidual tissue from
leads to extensive remodeling of the maternal spiral arterioles the women with preeclampsia also revealed defects in gene ex-
into high capacitance, high flow vessels.23 In placentas destined pression. These cells failed to redecidualize in culture, and their
to develop preeclampsia, cytotrophoblasts fail to transform conditioned medium failed to support cytotrophoblast invasion,
from the proliferative epithelial subtype to the invasive en- suggesting that decidual cells may be an important contributor
dothelial subtype which causes incomplete remodeling of the to downregulated cytotrophoblast invasion in preeclampsia.34
spiral artery.25 Inadequate spiral arteriolar remodeling leads to The in vitro studies are confirmed ex vivo in histological stud-
narrow maternal vessels, and relative placental ischemia.26 The ies of preeclampsia showing shallow placentation.31 Given the
narrow spiral arteries are prone to atherosis—characterized by mounting evidence of fetal and maternal abnormalities in pre-
the presence of lipid-laden macrophages within the lumen, fi- eclampsia, defective placentation might be the result of com-
brinoid necrosis of the arterial wall, and a mononuclear peri- binations of factors that affect both trophoblast and decidua.35,36
vascular infiltrate,27 leading to further compromise in placental
flow. In humans, placental ischemia can be noninvasively iden- Hypoxia and Trophoblast Invasion
tified using uterine artery Doppler studies. During normal Upregulation of hypoxia-inducible transcription factors (TFs)
pregnancy, uterine artery Doppler studies have confirmed ro- and hypoxia-related gene signatures in the placenta suggest
bust systolic and diastolic uterine arterial flows; in contrast, that hypoxia is central to the pathogenesis of preeclampsia.37
women with preeclampsia have significant impairment of di- In the early phases of implantation, the gestational sac exists
astolic flow with a characteristic notch in the waveform that in a low oxygen tension environment, favoring trophoblast
antedates clinical signs and symptoms of preeclampsia.28,29 proliferation. Before the invasion, the proliferating tropho-
These findings suggest that an abnormality in the trophoblasts blasts anchor the blastocyst to maternal tissues and plug the
themselves may result in shallow placentation and inadequate tips of the spiral arteries within the decidua.38 Eventually these
Rana et al   Preeclampsia and Vascular Disease   1097

Figure 1. Schematic of the pathogenesis of preeclampsia. Genetic factors, immunologic factors, other maternal factors cause placental dysfunction which
in turn leads to the release of antiangiogenic factors (such as sFLT1 [soluble fms-like tyrosine kinase 1] and sENG [soluble endoglin]) and other inflammatory
mediators to induce preeclampsia.
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trophoblastic-spiral artery plugs collapse, forming an intervil- maternal-fetal interface oxygen tension48,49 and may be useful
lous space. The newly formed sinuses allow for the arrival of for mapping areas of placental pathology and insufficiency.50
maternal blood, increasing oxygen tension, generating oxi-
dative stress, and promoting trophoblast differentiation from Oxidative Stress
a proliferative to an invasive phenotype that will invade and While low oxygen tension followed by maternal blood flow
remodel the spiral arteries.39 HIF (Hypoxia-inducible factors)- oxygenation results in normal placentation, intermittent hy-
1α and -2α, markers of cellular oxygen deprivation, are ex- poxia and reoxygenation caused by poor spiral artery invasion
pressed at high levels in proliferative trophoblasts and in the may cause oxidative stress. At the molecular level, preeclamp-
placentas of women with preeclampsia.40 Overexpression tic placentas show an imbalance of reactive oxygen species
of HIF-1α in pregnant mice is associated with hypertension,
proteinuria, and fetal growth restriction in mice41 and may
result in failure of trophoblastic differentiation from the pro-
liferative to the invasive phenotype.42 Furthermore, inhibition
of HIF-1α by 2-methoxyestradiol, a metabolite of estradiol
that destabilizes HIF-1α, suppresses the production of sFLT1
(soluble fms-like tyrosine kinase 1), a potent antiangiogenic
factor known to contribute to the maternal syndrome.43 HIF-
1α expression is regulated by many factors in addition to hy-
poxia, therefore, isolating the dysregulated signal upstream is
challenging.23,44 Magnetic resonance imaging has been used
to assess the placental perfusion fraction—an estimate of the
fraction of perfused tissue by volume—as a marker of uterine
flow or placental function.45–47 In a Swedish study of 35 women
with singleton pregnancies (13 with preeclampsia), Sohlberg
et al47 found a smaller placental perfusion fraction associated
with fetal growth restriction, as well as abnormalities in mater-
nal and fetal vessel doppler flow, neonatal weight, and plasma Figure 2. Decidual vasculopathy. Placental bed of the uterus with
decidual vasculopathy in the third trimester. Vessels show chronic injury
markers, including higher levels of sFLT1. Novel blood ox-
with endothelial fragmentation and detachment (arrow) and fibrinoid
ygen level-dependent magnetic resonance imaging responses necrosis (**) of the vessel wall. Scale bar is 100 μm. Reprinted from Hecht
promise new, noninvasive, in vivo techniques for assessing et al30 with permission. Copyright ©2016, Elsevier.
1098  Circulation Research  March 29, 2019

(ROS)-generating enzymes and antioxidants. In the ex vivo Another influence on trophoblastic invasion and spiral ar-
preeclamptic trophoblast, ROS-producing enzyme expres- tery remodeling may come from corin, a transmembrane en-
sion and activity are increased51 and inhibit the Wnt/β-catenin zyme that locally activates atrial natriuretic peptide through
signaling pathway that promotes trophoblast invasiveness.52 zymogen modification. Corin acts primarily in heart tissue,
Oxidative stress may also promote the transcription of an- however, Cui et al75 found significantly decreased uterine-lo-
tiangiogenic factors such as sFLT1.53 In humans, placental calized corin mRNA and protein levels as well as several corin
antioxidant mechanisms are impaired in patients with pree- gene mutations in preeclamptic patients. The group then creat-
clampsia, as shown by their decreased expression of super- ed a knockout corin rodent model as well as transgenic crosses
oxide dismutase and glutathione peroxidase compared with that retained isolated cardiac corin activity. Both phenotypes
women with normal pregnancies.54 However, treatment with mimicked the hallmarks of preeclampsia, independently of
the antioxidants Vitamin E and Vitamin C did not alter disease preexisting hypertension or cardiac-derived atrial natriuretic
in women with preeclampsia, suggesting that ROS may be peptide. However, in human studies, the evidence is mixed,
less integral to the pathway of the human syndrome.55,56 as systemic levels of corin and its target—atrial natriuretic
ROS may derive from mitochondrial stress. Zsengellér et peptide—are upregulated during preeclampsia76,77 not down-
al57 demonstrated decreased activity of the mitochondrial elec- regulated as would be expected based on the animal studies.
tron transport chain (ETC) enzyme cytochrome C oxidase in In earlier studies, women with hypertensive disorders of
the syncytiotrophoblast cells of preeclamptic placentas, which pregnancy were found to have lower levels of placental cate-
correlated with increased placental sFLT1 expression. Based chol-O-methyl transferase (COMT) enzyme,78 while women
on evidence that hydrogen sulfide donors inhibit HIF-1α,58 with normal gestations were found to have increasing concen-
Covarrubias et al59 demonstrated that AP39, a mitochondrial- trations of 2-methoxyestradiol, the COMT breakdown prod-
targeting hydrogen sulfide donor, pretreatment could decrease uct of estradiol.79 Based on these observations, Kanasaki et
sFLT1 expression in human syncytiotrophoblasts and increase al43 characterized a COMT knockout rodent model that repro-
cytochrome C oxidase activity in a dose-dependent fashion in duced the hallmarks of preeclampsia. However, COMT altera-
normal and preeclamptic placentas, preventing the release of tions are not a feature of severe early-onset preeclampsia in
ROS and the subsequent stabilization of HIF-1α.60 Recently humans.80 Given that COMT is decreased in many hyperten-
published studies with mitochondrial antioxidants in animal sive disorders of pregnancy,78 more evidence is required to im-
models of preeclampsia have also been promising.61 plicate COMT in the pathogenesis of preeclampsia rather than
Another possible source of oxidative stress is endoplasmic a risk factor for all gestational hypertensive disorders.
reticulum stress caused by ischemia-reperfusion injury.62,63
NK Cells and Impaired Placentation
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Endoplasmic reticulum stress has been observed in the de-


cidua and placentas of patients with fetal growth restriction The uterine NK (uNK) is well characterized in decidualization
and preeclampsia and triggers decidual cell and cytotropho- physiology81 and may play a role in the abnormal placenta-
blast apoptosis through the activation of the UPR (unfolded tion observed in preeclampsia. Unlike peripheral NKs, uNK
protein response).64,65 PERK (PKR-like endoplasmic reticulm is not cytotoxic.82,83 Rather, in the decidua, uNK cells regu-
kinase), a transmembrane kinase that decreases the transla- late the depth of placentation, spiral artery remodeling, and
tional burden of the endoplasmic reticulum and upregulates trophoblastic invasion.84,85 As the main immunologic player
proapoptotic TFs, has emerged as the leading signaling path- interacting at the allogenic maternal-fetal cell interface,81
way implicated in preeclampsia.64,65 Interestingly, a recent uNKs recognize self-major histocompatibility complexes
study suggests that synergy between ATF4 (activating tran- (MHCs) derived from the maternal contribution and nonself-
scription factor 4), a TF downstream of PERK, and ATF6, a allogenic MHCs from the paternal genotype. Specifically,
TF regulator of misfolded proteins in endoplasmic reticulum uNK express KIR (killer cell Ig-like receptors),86 while fe-
homeostasis,65,66 negatively regulate the transcription of PlGF tal invasive extravillous trophoblasts express the main KIR
(placental growth factor), an proangiogenic factor central to ligand, polymorphic HLA-C (human leukocyte antigen-C)
the pathogenesis of preeclampsia.67 MHCs.87 Because of independent segregation of maternal
KIR and HLA loci86 and the paternal contribution to extravil-
Heme Oxygenase and Other Enzyme Abnormalities lous trophoblast HLA-C, every pregnancy results in a unique
There is growing evidence that heme oxygenase (HO), the combination of KIR (maternal) and HLA-C (fetal) which may
heme degradation catalyst, has an important role in the vas- affect the success of placentation.83 Mouse models selected
cular function of the mother and the fetus, as well as in pla- for nonmatched maternal uNK and paternal MHC molecules
cental development and function.68–70 Three isoforms of HO in otherwise genetically identical parents have demonstrated
have been characterized,68,71 with HO-2 playing a role in spi- that allogenicity may promote decidual artery dilation, spiral
ral artery invasion72 and HO-1 highly expressed in noninvasive artery remodeling, more efficient placentas, and larger fetal
trophoblastic phenotypes.73 Treatment of the reduced uterine weights.88 In other words, inhibition of the uNK response by
perfusion pressure (RUPP) rodent model with CoPP (cobalt MHC-self recognition may lead to defective artery remodel-
protoporphyrin), an inducer of HO-1, decreased BP and result- ing.89 Furthermore, certain maternal KIR haplotypes (uNK)
ed in a proangiogenic shift in the VEGF (vascular endothelial appear protective against preeclampsia while others confer
growth factor)/sFLT1 ratio in the placenta.74 These preclinical risk.83,90–92 However, the presence of the risk-associated haplo-
studies have fueled interest in manipulating the expression of type is insufficient for disease, suggesting an additional envi-
HO-1 as a potential therapeutic intervention for preeclampsia. ronmental or genetic hit.
Rana et al   Preeclampsia and Vascular Disease   1099

Stage 2: Pathogenesis of the Maternal Syndrome women 2 months before the onset of clinical signs of pree-
clampsia, correlates with disease severity, and falls after
Imbalance in Circulating Angiogenic Factors
delivery.109,115 In pregnant rats, it appears to potentiate the
More than a decade ago, several groups identified elevated
vascular effects of sFLT1 to induce a severe preeclampsia-
levels of the antiangiogenic protein sFLT1 in placentas col-
like state, including the development of thrombocytopenia
lected from women with a clinical diagnosis of preeclamp-
and fetal growth restriction,116,117 and, in combination with
sia.93,94 sFLT1 is a soluble protein that exerts antiangiogenic
sFLT1, appears to induce cerebral edema resembling the re-
effects by binding to and inhibiting the biological activity of
versible posterior leukoencephalopathy seen in patients with
proangiogenic proteins VEGF and PlGF95 (Figure 3). VEGF
eclampsia.118,119
is important for the maintenance of endothelial cell function,
especially in fenestrated endothelium, which is found in the Inflammatory Cytokines and Immune Cell Alterations
brain, liver, and glomeruli, the primary organs affected by pre- It is well-established that preeclampsia is a proinflammatory
eclampsia.96 A member of the VEGF family, PlGF is impor- state, but the culpable cells have yet to be fully elucidated.
tant in angiogenesis and selectively binds to VEGFR1/sFLT1 Syncytial knots120,121 are allogenic nano to microvesicles shed
not VEGFR2.97 Several findings implicated sFLT1 in the path- from apoptotic or activated trophoblasts121 that have been
ogenesis of preeclampsia: sFLT1 protein levels were high in identified in the lungs120,122 and plasma of normal pregnan-
maternal plasma or serum94,98; sFLT1 mRNA expression was cies and in increased amounts in preeclampsia.122–124 Rich in
high in preeclamptic placentas99; and injecting exogenous sFLT1 and endoglin,125,126 syncytiotrophoblast microvesicles
sFLT1 into rodents led to hypertension, proteinuria, glomer- and exosomes may instigate an inflammatory response. In
ular endotheliosis (a hallmark of preeclampsia seen in renal vitro, syncytiotrophoblast microvesicles activate cultured pe-
biopsy), as well as several other preeclamptic features94,100; ripheral blood mononuclear cells, causing a release of pro-
treatment of cancer patients with anti-VEGF drugs results in inflammatory cytokines124,127 that is even more robust when
hypertension and proteinuria101,102; depletion of sFLT1 in pre- exposed to peripheral blood mononuclear cells from preg-
eclamptic plasma using antibodies reverses the antiangiogenic nant patients.127 However, in vitro data are not consistent, as
phenotype in cell culture studies93; lowering sFLT1 or antago- microvesicles induced by an alternative mechanism are not
nizing sFLT1 in animal models of preeclampsia improves proinflammatory.128,129
clinical symptoms103–105 and, spontaneous resolution of clin- IL (Interleukin)-10—a cytokine that induces the differen-
ical signs and symptoms of preeclampsia, when sFLT1 levels tiation of the T cell into the Th (T helper type)2 phenotype—
are lowered by 50% or more by treatment of the underlying stands out in the literature as an important mitigator of the
placental conditions such as fetal hydrops or removal of dis- maternal syndrome by neutralizing proinflammatory cyto-
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eased placenta in multiple pregnancies.106,107 In addition to the kines, AT1-AA (angiotensin II receptor 1 autoantibodies),
elevated sFLT1 levels, circulating levels of free PlGF were re- placental ROS, and ET-1 (endothelin-1).130 Many cell types
duced in women with preeclampsia, suggesting an imbalance in preeclamptic patients demonstrate a dysregulation in the
of antiangiogenic and proangiogenic proteins.94,108 balance of IL-10 and proinflammatory cytokines,131–133 includ-
The availability of robust immunoassays for angiogenic ing uterine and circulating NKs134 and peripheral blood mon-
factors led to a number of clinical studies measuring the anti- onuclear cells. Studies of peripheral blood mononuclear cells
angiogenic/proangiogenic markers in large cohorts of human of preeclamptic women had reduced IL-10 secretion,135–138
pregnancies showing that sFLT1 levels are high and free PlGF which may lead to failure of T-cell differentiation. Commonly
is low at the time of clinical diagnosis of preeclampsia as well referred to as Th2 polarization, normal pregnancy is charac-
as several weeks before the diagnosis.108,109 Angiogenic factor terized by a shift in T-cell phenotype towards Th2 relative to
abnormalities in the plasma correlated with severity of presen- Th1.139,140 Multiple studies have reported an aberrant shift to-
tation, predicting disease, and adverse outcomes.110,111 Early wards the Th1 phenotype in preeclampsia, resulting in insuffi-
studies called into question the utility of angiogenic factors cient trophoblast invasion.141 Furthermore, a preeclamptic-like
in prediction of preeclampsia.112 However, a recent multisite, syndrome can be induced in normal pregnant rats with transfer
blinded randomized trial for the use of aspirin for prevention of CD4+ cells obtained from RUPP models.122
of preeclampsia used several physiological and biochemical Preeclampsia is also associated with elevated comple-
parameters, including PlGF, with a detection rate of 90% at ment levels142,143 and with genetic mutations in C3.144 In an-
a fixed false positive rate of 5% for preeclampsia, suggesting imal models, complement inhibition restores spiral artery
that the markers may be used algorithmically for early diagno- capacitance145 and decreases sFLT1 production,146 and a C1q
sis.113 Such a strategy for prediction of the syndrome in early knockout mouse model mimics preeclamptic features.147,148
pregnancy would identify women who are at risk for develop- However, complement dysregulation is most severe in the
ing the disease and who may benefit from preventative inter- form of severe preeclampsia called hemolysis elevated liver
ventions such as aspirin. Early diagnosis would also reduce enzymes low platelets (HELLP) syndrome. HELLP syndrome
anxiety and unnecessary interventions in women at otherwise has been shown to share a genetic mutation with149 and has a
low risk of developing preeclampsia. similar presentation to atypical hemolytic uremic syndrome,
Another antiangiogenic protein that has also been exten- a disease thought to be caused by uncontrolled complement
sively studied in preeclampsia is soluble endoglin (sENG), an activation.150–152 Interestingly, many of the same complement
endogenous TGF-β1 (transforming growth factor β1) inhibi- pathway mutations found in hemolytic uremic syndrome are
tor114 (Figure 3). sENG is elevated in the sera of preeclamptic also associated with preeclampsia.142,150 Further evidence to
1100  Circulation Research  March 29, 2019

Figure 3. sFLT1 (soluble fms-like tyrosine kinase 1) and sENG (soluble endoglin) causes endothelial dysfunction by antagonizing VEGF (vascular
endothelial growth factor) and TGF (transforming growth factor)-β1 signaling. There is mounting evidence that VEGF and TGF-β1 are required to
maintain endothelial health in several tissues including the kidney and perhaps the placenta. During normal pregnancy, vascular homeostasis is maintained
by physiological levels of VEGF and TGF-β1 signaling in the vasculature. In preeclampsia, excess placental secretion of sFLT1 and sENG (2 endogenous
circulating antiangiogenic proteins) inhibits VEGF and TGF-β1 signaling respectively in the vasculature. This results in endothelial cell dysfunction, including
decreased prostacyclin, nitric oxide production, and release of procoagulant proteins. Reprinted from Powe et al114 with permission. Copyright ©2011, the
American Heart Association.

the pathogenic link between atypical hemolytic uremic syn- patients, implicating B lymphocytes as an immune player.170
drome and HELLP, a patient presenting with early-onset se- These findings suggest that anti-AT1-AA made by a subpopu-
vere preeclampsia and HELLP was able to delay delivery by lation of CD19+CD5+ in response to placental ischemia and
Downloaded from http://ahajournals.org by on April 15, 2019

17 days after treatment with Eculizumab,153 an Food and Drug systemic inflammation may contribute to the hypertension and
Administration-approved C5 inhibitor used to treat atypical production of antiangiogenic factors that characterize the ma-
hemolytic uremic syndrome 154,155 including in pregnancy.156 ternal syndrome.
The use of Eculizumab as an effective treatment for a severe Recent preclinical studies on the hypersensitivity of the
form of preeclampsia is promising, however, HELLP is di- AT1 receptor when complexed with the bradykinin B2 re-
agnostically difficult to distinguish from atypical hemolytic ceptor provide compelling evidence for another model for
uremic syndrome,157 likely because of the overlap in comple- the activation of the renin-angiotensin-aldosterone system in
ment pathology. the setting of downregulated renin.171 Using a new transgenic
mouse model with maternal, systemically upregulated smooth
Renin-Angiotensin Pathway muscle AT1-B2 complexes, the group was able to replicate
There is evidence for alterations in the renin-angiotensin- the preeclampsia syndrome, with pregnant animals develop-
aldosterone system in the pathogenesis of preeclampsia.158 ing hypertension, proteinuria, low platelets, increased sFLT1,
Several studies show enhanced angiotensin II sensitivity dur- AT1-AA, and ET-1, smaller litter sizes, intrauterine growth
ing and before the onset of preeclampsia despite reduced cir- restriction, lower renin levels, and a decreased placental lab-
culating renin and angiotensin II during preeclampsia when yrinth layer. Furthermore, when heteromerized with B2, ATI
compared with normal pregnancy.159,160 One potential mechan- seems independently sensitive to angiotensin II and mechano-
ism for the increased angiotensin II sensitivity is the presence stimulation, which, the authors suggest, may evolve with an
of circulating autoantibodies to AT1 in the sera of preeclamp- increase in fetal-placental mass regardless of renin activity.
tic women.161,162 In preclinical studies, autoantibodies to AT1 The preeclamptic-like transgenic mice were then rescued with
reproduce many of the hallmark characteristics of preeclamp- lentiviral administration of an inactivation-resistant variant of
sia: vasoconstriction through activation of ET-1163; endothelial Arrb1 (β-arrestin-1), G-protein coupled receptor-associated
cell necrosis and apoptosis in human umbilical vein endothe- protein that desensitizes the AT1 receptor leading to signal
lial cells164; stimulation of tissue factor production contribut- dampening. In ex vivo studies of human placentas, the group
ing to hypercoagulation165; reduction of trophoblast invasion found significantly elevated levels of inactivated (phosphory-
in human cell culture models166; and increased production of lated) levels of Arrb1 in preeclamptic placentas compared
ROS in culture models.167 Produced in response to placen- with normotensive placentas, as well as increased AT1-B2
tal ischemia and systemic inflammation,168 anti-AT1-AA can complex formation on the vessels of the basal plate of a pre-
also stimulate placental production of antiangiogenic factors eclamptic placenta. Though the AT1-B2 model does appear
sFLT1 and sENG.169 Finally, CD19+CD5+ cells, as well as to replicate the maternal syndrome well, only a small num-
anti-AT1-AA activity, are elevated in the sera of preeclamptic ber of human placentas were analyzed as part of this study.
Rana et al   Preeclampsia and Vascular Disease   1101

Additional human studies are required to assess applicability have been used as well. Mildly hypertensive at baseline, the
of this model to the biology of preeclampsia. BPH/5 model demonstrates elevated mean arterial pressure,
Elevated levels of an oxidized form of angiotensinogen proteinuria, and progressive glomerular damage in late gesta-
that is more readily cleaved by renin have also been impli- tion and delivers significantly smaller litters than controls.183
cated in the pathogenesis of the hypertension observed in pre- The previously discussed COMT knockout rodent model sim-
eclampsia.172 However, robust assays to measure this modified ilarly presents with systolic hypertension, elevated sFLT1, and
form of angiotensinogen in the blood are needed to charac- proteinuria that decline after parturition, however, there is no
terize a role for oxidized angiotensinogen in preeclampsia. evidence of systemic vascular damage or fetal growth restric-
Finally, in animal models, elevated levels of circulating sFLT1 tion, suggesting that this model approximates gestational hy-
were sufficient to induce angiotensin II sensitivity by inter- pertension or mild preeclampsia.43 The C1q knockout mouse
fering with endothelial nitric oxide production.173 model relies on the observation of the complement factor C1q
at the decidual endothelium-trophoblast interface184 and was
Sympathetic Nervous System
found to have small litters, intrauterine growth restriction, el-
While a major emphasis of study in the pathogenesis of pre-
evated BP, proteinuria, elevated levels of sFLT1, and evidence
eclampsia has been on the link between placental factors and
of endothelial dysfunction.147,148 Systemic delivery of argi-
maternal endothelial dysfunction, several studies have im-
nine vasopressin was also sufficient to induce preeclampsia-
plicated the sympathetic nervous system in the pathogenesis
like state in pregnant mice, but lack of placental hypoxia and
of preeclampsia.174,175 Schobel et al174 observed that muscle
sFLT1 upregulation in this model suggest that it may be more
sympathetic nerve activity is elevated in women with pree-
relevant for term preeclampsia that is often characterized by
clampsia over normal pregnant and hypertensive, nonpregnant
modest levels of antiangiogenic biomarkers.185 Older rodent
control women. Women with preeclampsia also have reduced
models manipulate the renin-angiotensin system (placental
baroreflex sensitivity and greater antihypertensive responses
renin and maternal angiotensinogen) to model pregnancy-in-
to nonselective adrenergic receptor blockade.176,177 Studies
duced hypertension,186 however, the relevance of this model to
using experimental animal models supports that sympathetic
human disease is questionable as humans with preeclampsia
nerve activity is increased in preeclampsia. Placental isch-
are characterized by suppressed renin and angiotensin II when
emia-induced hypertension in the RUPP rat model is associ-
compared with normal pregnancy.
ated with a hypertensive shift in baroreceptor control on renal
Primarily designed on the observation that placental is-
sympathetic nerve activity, 178 and a recent study found that
chemia induces systemic hypertension, the described animal
adrenergic receptor blockade markedly attenuates placental
models have been useful for characterizing the molecular en-
ischemia-induced hypertension.179 Collectively, studies from
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vironment of uteroplacental hypoperfusion as well as a variety


humans and animal models suggest that an intact sympathetic
of cytokines and proteins released into the maternal circula-
nervous system may be important in eliciting the full hyper-
tion. Animal models can be used to extend correlation data
tensive response to factors released in response to placental
observed in humans into cause and effect relationships, as has
ischemia.
been seen in sFLT1 and sENG manipulation in RUPP mod-
Lessons From Animal Models els, and are critical tools for assessing toxicity and efficacy
One of the many challenges of the study of preeclampsia is in novel therapeutics. Of course, animal models are imperfect
its reproducibility in animal models. Spontaneous preeclamp- for this human-specific disease, as they fail to demonstrate
sia is unique to human gestation. Therefore, animal models thrombocytopenia, HELLP syndrome, eclamptic seizures,
approximate rather than replicate the disease, predominantly and other signs and symptoms that define the severe features
through evidence of systolic hypertension, renal endothelio- of preeclampsia in humans. Perhaps, the imperfect overlap
sis, proteinuria, and, at times, fetal growth restriction and pro- in presentation stems from the fact that the primary driver
duction of antiangiogenic factors.180 The RUPP rodent model, of preeclampsia, insufficient trophoblast invasion and failure
produced by clipping the abdominal aorta and the main uter- of spiral artery remodeling, does not occur naturally in other
ine arteries of pregnant Sprague-Dawley rats,181 is most com- species and has yet to be modeled accurately. In fact, rodent
monly used and presents with elevated mean arterial pressure, trophoblasts minimally invade the spiral arteries, as decidu-
greater vascular reactivity to α-adrenergic agonists181 and in- alization occurs after implantation,187 and therefore, may be
creased production of AT1-AA, ROS, and sFLT1 and sENG an inherently insufficient model species. Furthermore, human
as observed in preeclamptic women.182 Other animals, includ- gestation is significantly longer than in rodents, and exposes
ing pregnant rabbits, rhesus monkeys, and baboons, have also pregnant women to much larger doses of circulating toxins,
been used to model preeclampsia by inducing uteroplacental such as sFLT1, possibly leading to severe features. In fact,
insufficiency.182 To replicate the placenta as the inherently when sFLT1 and sENG levels are concurrently pushed to
pathogenic organ rather than as secondary to uterine ische- exaggerated levels, severe features do occur in animal mod-
mia, Kumasawa et al104 implanted mice with transgenic blas- els.108–110,113 Despite their limitations, experimental studies in
tocysts with trophectodermal layers expressing human sFLT1 animal models allow investigators to test directly whether
via lentiviral vectors. Human sFLT1 levels increased in the certain factors found in women with preeclampsia can in-
maternal serum as gestation progressed, with corresponding deed lead to hypertension and other manifestations of the
development of the hallmarks of preeclampsia. However, the syndrome. Further investigation is necessary with models that
rodents did not develop the full spectrum of severe features as better approximate human gestation physiology and length to
in humans. Genetic rodent models, such as the BPH/5 model, isolate the primary pathogenic factors.
1102  Circulation Research  March 29, 2019

Maternal Contribution to Disease and detection rate of preterm preeclampsia was 76.7%
Epidemiological studies suggest that several prepregnancy (138/180)—43.1% for term preeclampsia—with a false pos-
maternal characteristics increase risk for preeclampsia.188 itive rate of 9.1%. These results suggest that early screening
Interest is growing around obesity and diabetes mellitus as with plasma biomarkers and imaging studies allows for early
risk factors (relative risk [RR], ≈3.5 each)189 in light of data intervention and possible prevention of disease.
suggesting Metformin, the biguanide first-line therapy for Perhaps most promising among screening methods is the
type 2 diabetes mellitus, may decrease sFLT1.190 In a recent use during the third trimester of combined biomarkers—such
meta-analysis of 15 randomized controlled trials reporting as sFLT1, sEng, and PlGF—with high sensitivity and spec-
the incidence of hypertensive disorders of pregnancy with ificity for early diagnosis and prognosis of preeclampsia.200
Metformin use, Kalafat et al191 found a reduced risk of hyper- Substantial evidence already demonstrates encouraging test
tensive disorders of pregnancy (RR, 0.56; 95% CI, 0.37–0.85) characteristics of biomarker assays in this population.201,202 In
but a nonsignificantly reduced risk of preeclampsia (RR, 0.74; a study of over 600 women undergoing initial evaluation of
95% CI, 0.09–6.28). However, authors admit the low quality preeclampsia, an sFLT1/PlGF ratio of ≥85 correlated with di-
of the evidence and the clinical heterogeneity of the included agnosis of preeclampsia and predicted adverse outcomes and
studies, limiting conclusions. Prepregnancy vascular dysfunc- delivery within 2 weeks among women presenting <34 weeks
tion, such as in women with chronic hypertension, not only gestation. Furthermore, the biomarker ratio performed better
jeopardizes placental perfusion but may also enhance the pla- than all other currently available tests for prediction of pree-
cental response to ischemia as well as the vascular response clampsia.110 A follow-up study of 402 patients presenting with
to antiangiogenic factors such as sFLT1. Therefore, baseline preterm singleton pregnancies by the same group showed that
host characteristics may put women at risk of preeclampsia, an sFLT1/PlGF ratio >85 had a PPV of 59% in all patients and
even at physiological elevations of antiangiogenic factors 74% among patients presenting <34 weeks for developing pre-
and cytokines. A history of acute kidney injury before preg- eclampsia with severe features within 2 weeks.203 Patients with
nancy, despite apparent full recovery, is also associated with preeclampsia with normal angiogenic profile have fewer ad-
increased risk of pregnancy complications.192 Interestingly, a verse outcomes suggesting that the angiogenic form of pree-
shorter interval between the AKI episode and the pregnancy clampsia is clinically more important.111 Other groups have
were associated with higher risks of preeclampsia. This sug- shown similar results. In a multicenter study of women with
gests that subclinical renal dysfunction may interfere with the suspected preeclampsia, authors showed a reverse association
hemodynamic adaptation of normal pregnancy, which in turn of free PlGF with gestational age at delivery.204 In a recent mul-
may lead to impaired placental perfusion and preeclampsia.192 tisite study of angiogenic factors, authors concluded that an
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sFLT1/PlGF ratio of ≤38 had an negative predictive value of


Translation of Preeclampsia 99.9% for ruling out preeclampsia within 1 week.205 A follow-up
Biology in the Clinic study from the same cohort showed an negative predictive value
of 95% within 4 weeks.206 Overall, serum or plasma angiogenic
Biomarkers for Diagnosis, Prediction, factors appear to be a reliable risk-stratification method among
and Prognosis women with suspected preeclampsia, especially for  preterm
The ACOG committee opinion issued in 2015 and reaffirmed preeclampsia, allowing for appropriate management.
in 2017 does not recommend screening to predict preeclamp- Recent studies have also suggested that by reducing false
sia beyond obtaining an appropriate medical history.18,193 positive rates of diagnosis and consequent unnecessary hospi-
Because of the lack of adequate screening methods and the talizations, risk stratification with biomarkers is economical.
severe sequelae of the disease, all women suspected of pree- Assays using these plasma biomarkers are available for clini-
clampsia undergo resource intensive testing, often requiring cal use in Europe, Canada, Africa, and Asia, and their clinical
several-day hospitalizations for further investigation. Other success has led to the incorporation of angiogenic factors in
methods of screening have been investigated, including a me- the definition of preeclampsia in the British National Institute
tabolomic pathways and combined metabolomic-proteomic for Health and Care Excellence and national German guide-
data approaches.194–197 A 2017 head to head comparison of the lines.207 Finally, a study in Mozambique showed that meas-
Fetal Medicine Foundation algorithm-based screening method urement of PlGF is feasible in resource poor environments.
(a combination of maternal factors, mean arterial pressure, The authors concluded that low PlGF in women with sus-
uterine-artery pulsatility index, and PlGF) demonstrated su- pected preeclampsia was associated with increased transfers
periority to the screening methods currently recommended to higher levels of care and increased maternal and perinatal
by National Institute for Health and Care Excellence and risks.208 Looking forward, biomarker assays are a cost-effec-
ACOG.198 Using a similar screening algorithm with the addi- tive and reliable screening method that could be lifesaving,
tion of maternal serum PAPP-A (pregnancy-associated plasma even in areas of limited expertise and resources.
protein-A), the ASPRE trial (aspirin for evidence-based pre- Though not part of any formal diagnostic criteria, hyper-
eclampsia prevention) screened women in the first trimester uricemia is classically a biomarker indicating progression of
to identify those at high risk for preeclampsia.199 High-risk gestational or chronic hypertension to preeclampsia and of
women were then randomized to receive 150 mg of aspirin risk for fetal and maternal complications such as SGA.209–212
or placebo daily until 36 weeks gestation. Daily low-dose as- However, in all-comers, uric acid levels do not predict devel-
pirin use in high-risk women was associated with a signifi- opment of preeclampsia.213–215 Evidence about the contribu-
cantly lower incidence of preterm preeclampsia than placebo, tion of uric acid to the pathogenesis of preeclampsia is mixed,
Rana et al   Preeclampsia and Vascular Disease   1103

though general consensus suggests that levels are elevated Maternal STRIDER trial (Sildenafil for Severe Fetal Growth
secondary to renal injury and decreased excretion.216 Restriction), sildenafil did not prolong pregnancy or improve
pregnancy outcomes compared with placebo in women with
Treatment and Management of Preeclampsia severe intrauterine growth restriction in the late second to
Current management of preeclampsia in the developed world third trimester.220 A 2017 randomized controlled trial of sil-
includes preconception counseling, perinatal BP control and denafil therapy in fetal growth restriction did not show any
monitoring, prenatal aspirin therapy in high-risk women, be- benefit in attenuating disease compared with placebo221 and
tamethasone for patients <34 weeks, parenteral magnesium was prematurely halted when 11 neonates in the sildenafil arm
sulfate, and careful follow-up of postpartum BPs.1 Timely died secondary to pulmonary disease.222 However, other small
delivery of the fetus and placenta remains the only definitive molecules that effect nitric oxide production are still under
treatment. Even among patients who did not show antena- investigation. For example, statins continue to show promise
tal signs of preeclampsia, surveillance continues postpartum in animal models and in human ex vivo tissue samples.223–225
because of the rising incidence of postpartum preeclampsia. Likely because of its stimulatory effects on HO and improved
Preeclampsia without severe features can be managed expect- vascular function,224 pravastatin improves fetal and mater-
antly with twice-weekly maternal and fetal monitoring until nal outcomes in patients with antiphospholipid syndrome226
37 weeks in the absence of labor, rupture of membranes, vag- and mitigates disease in patients with severe features225 and
inal bleeding, or abnormal antepartum testing.1,18 In women with evidence of placental vascular pathology.227 StAmP trial
with preeclampsia with severe features at <34 weeks, expect- (Statins to Ameliorate Early Onset Preeclampsia), a dou-
ant management can be attempted based on strict inclusion ble-blind, multicenter, randomized controlled trial looking at
criteria and with appropriate resources. In these patients, care- the effects of Pravastatin on serum biomarkers in preeclamp-
ful attention should be given to worsening maternal and fetal sia, has completed recruitment and is now in the data-analysis
well-being and delivery is indicated at any time with deterio- phase (ISRCTN 23410175). Metformin, an insulin sensitizer
ration of maternal and fetal status. ACOG currently does not and the first-line treatment of type 2 diabetes mellitus, is as-
recommend pharmacological treatment of mild to moderate sociated with reduced incidence of hypertensive disorders in
range hypertension (systolic <160 mm Hg or diastolic <110 pregnancy,191 as well as decreased levels of circulating sFLT1
mm Hg) in the setting of preeclampsia,1 as it does not appear and sENG in vitro.228 Metformin has been shown to be safe in
to attenuate risk of disease progression and may increase the pregnancy, with no significant difference in neonatal outcomes
risk of fetal growth restriction.217 In a multinational random- when compared with insulin in the treatment of gestational di-
ized trial for control of BPs enrolling women with chronic and abetes mellitus,229 making Metformin an attractive and readily
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gestational hypertension, authors found lower prevalence of available therapy. Finally, ouabain, a cardiac glycoside, has
severe hypertension (≥160/110 mm Hg) among patients with been shown to inhibit sFLT1 mRNA and protein expression
tight control of BPs during pregnancy (40.6% versus 27.5%). through the HIF-1α/heat-shock protein 27 pathway in human
There was no difference in development of preeclampsia and cytotrophoblasts and explant cultures as well as in rat mod-
perinatal outcomes were similar.218 A large randomized trial is els without any fetal adverse effects.230 Further investigation
underway in the United States to evaluate treatment of mod- is necessary to further characterize ouabain as a therapeutic.
erate hypertension during pregnancy (URL: http://www.clini- Most small molecules target the prevention of preeclamp-
caltrials.gov. Unique identifier: NCT02299414). Treatment of sia in high-risk women, however, no therapy currently exists
severe hypertension requires pharmacological therapy with la- for the treatment of preeclampsia to delay preterm delivery.
betalol, nifedipine, or methyldopa,1 however, recent evidence Adapting apheresis technology safely and commonly used
from animal studies suggest that amlodipine may be superior in pregnant women with familial hypercholesterolemia,231
to nifedipine because of its inducing effects on Arrb1 and sub- Thadhani et al232 used a negatively charged dextran sulfate cel-
sequent downregulation of the AT1-B2 receptor complex,171 lulose column to remove positively charged sFLT1 from the
though more clinical evidence is needed. Though current clin- serum of 3 women with preterm (<32 weeks) preeclampsia,
ical management is limited, innovative medical therapies are resulting in dose-dependent delays in delivery. To minimize
on the horizon. the side effect profile—namely, transient hypotension—and
Small molecules have had variable success in treating hy- improve the efficiency of removal, the same group repeated
pertensive disorders of pregnancy. Early studies, including the the pilot study with an apheresis device that incorporated
1998 National Institutes of Health trial, did not show improved plasma separation for sFLT1 removal.233 Eleven women with
outcomes in women at high risk of preeclampsia when treated very preterm preeclampsia were treated with dextran sulfate
with low dose (60 mg) of aspirin compared with placebo.219 column apheresis with a mean reduction in sFLT1 of 18% per
However, with improved risk-stratification methods, Rolnik et treatment and an average of 8 days (range 2–11) of extended
al199 demonstrated a lower incidence of preterm preeclampsia gestation with a single treatment and an average of 15 days
in high-risk women treated with 150 mg of aspiring compared (range 11–21) extended gestation with multiple treatments,
with placebo. Aspirin is now recommended for the prevention compared with an average of 3 to 4 days in controls. There
of preeclampsia in high-risk women.1 were no additional adverse events in neonates treated with
Sildenafil, a phosphodiesterase type 5 inhibitor, was ini- apheresis compared with normal and preeclamptic controls
tially thought to be a promising way to reduce placental is- born comparably preterm. Direct therapies for the treatment
chemia given its ability to potentiate the actions of nitric of preeclampsia would revolutionize the management of this
oxide, causing uterine vasodilation. However, in the 2018 highly morbid disease, and the results from these pilot studies
1104  Circulation Research  March 29, 2019

show immense promise, with refinement of the specificity of fluid in women with preeclampsia.242 Epidemiological stud-
the apheretic column for known preeclamptic markers. ies have shown an increased incidence of bronchopulmona-
Other promising therapies for preeclampsia include recom- ry dysplasia243,244 and decreased incidence of retinopathy of
binant human PlGF and RNA interference technology-based prematurity (adjusted odds ratio 0.65; 95% CI, 0.49–0.86
methods. A ligand specific to VEGFR1/Flt1, recombinant for early preterm),245 2 diseases of prematurity associated
human PlGF has the potential to scavenge excess circulating with neoangiogenesis. Intraamniotic injections of sFlt1 in
sFLT1 without the additional side effects of vascular permea- rat models disrupt pulmonary angiogenesis and increase
bility and edema associated with VEGFR2. Baboon and rodent the incidence of bronchopulmonary dysplasia,244 while ad-
studies have shown promising results, lowering BP, proteinu- ministration of anti-sFLT1 monoclonal antibody increases
ria, and sFLT1 mRNA.234,235 However, the treatment may be alveolar counts and pulmonary vessel density in the pre-
limited given that only a small percentage of total body sFLT1 mature pups of preeclampsia rat models.246 Together, these
is circulating236 and, therefore, amenable to ligand interaction. epidemiological and animal studies imply that sFLT1 af-
RNA interference technology provides a cheaper alternative fects fetal angiogenesis at mucous membranes exposed to
to recombinant therapies. Silencing sequences of RNA spe- amniotic fluid.
cific to all 3 isoforms of circulating sFLT1 mRNA have been
shown to decrease sFLT1, BP, and proteinuria in pregnant ba- Preeclampsia and Long-Term CVD
boon models with a single dose.237 However, given the limi- There is accumulating evidence that preeclampsia-eclampsia
tations of animal models of preeclampsia and the regulatory predisposes to long-term cardiovascular risk247,248 including
implications of developing oligonucleotide therapies, signifi- risk of hypertension, peripheral arterial disease (RR, 1.87;
cant further study is required before clinical trials. 0.94–3.73), coronary artery disease (overall CVD RR: 2.3;
1.95–2.78), cerebrovascular disease (RR, 2.03; 1.54–2.67),
Preeclampsia and CVD congestive heart failure, vascular dementia (hazard ratio, 3.46;
1.97–6.10), and death (RR, 2.29; 1.73–3.04).248–250 Potential
Short-Term Cardiovascular Complications in the explanations for the association between preeclampsia and
Postpartum Period CVD are debated. It has been proposed that endothelial dam-
Postpartum hypertension (defined as hypertension >48 hours age caused by preeclampsia persists beyond postpartum re-
or more after delivery) occurring either de novo or in the set-
covery, increasing the risk of CVD,247 and that the risk of
ting of preeclampsia has emerged as an important risk fac-
future CVD increases with multiple episodes of preeclamp-
tor for significant morbidity in women in the United States.238
sia.248 Alternatively, an unfavorable cardiovascular risk profile
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While the pathogenesis of this syndrome is still being elucidat-


characterized by higher levels of glucose, cholesterol, hyper-
ed, clinical studies have suggested that postpartum hyperten-
tension, and abdominal obesity may contribute to the develop-
sion may share similar plasma angiogenic profiles as women
ment of preeclampsia and later, CVD.249
with antepartum preeclampsia and, therefore, may represent a
The odds of a fatal outcome from CVD have been shown
group of women with subclinical preeclampsia or unresolved
to be greater than odds of diagnosis (odds ratio =2.89; 95%
preeclampsia.5 In the peripartum period, preeclampsia is as-
CI, 1.71–4.89 and odds ratio =2.01; 95% CI, 1.68–2.41; re-
sociated with an increased risk of peripartum cardiomyopa-
thy (PPCM) that can progress to chronic heart failure, cardiac spectively)250 in preeclampsia, suggesting that women may
transplantation, or death.239,240 Given that VEGF pathway in- die from the sequelae of CVD without first being diagnosed.
hibitors in oncology patients also induce cardiomyopathy,241 Furthermore, meta-regression reveals a graded relationship
elevated levels of antiangiogenic factors may play a role in between the severity of preeclampsia-eclampsia and the risk
the development of PPCM. Using a PGC (proangiogenic tran- of cardiac disease (mild: RR 2.00, 1.83–2.19; moderate: RR
scriptional cofactor)-1α knockout mouse model and human 2.99, 2.51–3.58; and severe: RR 5.36, 3.96–7.27; P<0.0001),
serum studies, Patten et al240 showed that repeatedly elevated implicating a dose-response to the severity of preeclamp-
levels of sFLT1 and prolactin cleavage fragments were syn- sia.249 Studies are underway to find biomarkers and subclin-
ergistically associated with PPCM and that both angiogenic ical echocardiographic measures, such as global longitudinal
factor imbalance and prolactin fragmentation are regulated strain,251–253 to provide early risk assessment and stratification
by PGC-1α. Authors proposed a 2-hit hypothesis for the de- in women with preeclampsia.
velopment of PPCM: (1) an increase in antiangiogenic fac- The question remains if there is an opportunity for inter-
tors such as sFLT1 that causes cardiac dysfunction as seen vention in asymptomatic women with a history of preeclamp-
in preeclampsia and (2) an independent decrease in defenses sia. A study of 2 tertiary medical centers in the Netherlands254
against antiangiogenic factors in the heart as seen in low levels found that a total of 42% of women with a history of pre-
of cardiac PGC-1α expression. Thus, inhibition or removal of eclampsia had significant CVD risk factors compared with
sFLT1 could attenuate PPCM in preeclamptic women with an 14.3% among women with a history of an uncomplicated
environmental or genetic predisposition to disease. pregnancy. In the United States, a 2018 study using the
In the short-term, neonates may also present with Nurses’ Health Study II suggested that hypertensive disorders
vascular effects secondary to the elevated levels of anti- of pregnancy were associated with 10-year CVD risk overall,
angiogenic factors. Though hypertension and proteinuria independent of established CVD risk factors. Globally there is
observed in the mother are not observed in the fetus, ele- increasing evidence that a history of preeclampsia should be
vated levels of sFLT1 have been observed in the amniotic considered in CVD risk stratification.7
Rana et al   Preeclampsia and Vascular Disease   1105

Preeclampsia is also associated with 4.7-fold risk for subse- alternatives to preterm delivery. Most importantly, risk-strat-
quent end-stage renal disease.255 Based on sibling studies, Vikse ification methods using antiangiogenic factors have already
et al256 reported that familial aggregation of risk factors could not proven to be safe, efficient, cost-effective, and economical,
explain the increased end-stage renal disease risk and, therefore, making them possibilities for improving care in countries that
concluded that preeclampsia per se may lead to long-term kid- carry the highest mortality from preeclampsia.
ney damage. Women with preeclampsia are also at a 4-fold risk
of stroke257 and 3-fold risk of vascular dementia later in life.258 Disclosures
Additional studies are needed to elucidate the pathogenesis of S. Rana reports serving as a consultant for Roche Diagnostics and
these long-term complications in women with preeclampsia. Thermofisher and has received research funding from Roche and
Decades of literature observe a relationship between life- Siemens. Dr Karumanchi is colisted as coinventors on patents re-
lated to preeclampsia biomarkers and therapies that are held at
long CVD risk and growth restriction in utero, such as seen Beth Israel Deaconess Medical Center. He has a financial inter-
in the fetuses of preeclamptic pregnancies. First described est in Aggamin LLC and also reports serving as a consultant to
by Barker and Osmond,259 the so-called Barker Hypothesis Thermofisher.He has received research funding from Siemens. The
suggests that lack of early nutrition, growth restriction, and other authors report no conflicts.
the uterine environment increase susceptibility to other risks
for CVD. Indeed, children born to women with preeclamp- References
sia have an increased risk of CVD.260 Neonates may also be 1. American College of Obstetricians and Gynecologists; Task Force on
Hypertension in Pregnancy. Hypertension in pregnancy. Report of the
at risk for pulmonary hypertension into their teenage years American College of Obstetricians and Gynecologists’ Task Force on
and beyond.261 Pulmonary amniotic sFLT1 exposure leading Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–1131. doi:
to decreased pulmonary angiogenesis has been proposed as 10.1097/01.AOG.0000437382.03963.88
2. Hogan MC, Foreman KJ, Naghavi M, Ahn SY, Wang M, Makela
a mechanism for this long-term lung injury,246 though the se-
SM, Lopez AD, Lozano R, Murray CJ. Maternal mortality for 181
quelae of prematurity or systemic sFLT1 exposure246 cannot countries, 1980-2008: a systematic analysis of progress towards
be excluded. Current research seeks to further characterize Millennium Development Goal 5. Lancet. 2010;375:1609–1623. doi:
CVD in children born to preeclamptic mothers.262 10.1016/S0140-6736(10)60518-1
3. Wanderer JP, Leffert LR, Mhyre JM, Kuklina EV, Callaghan WM,
Bateman BT. Epidemiology of obstetric-related ICU admissions in
Conclusions Maryland: 1999-2008*. Crit Care Med. 2013;41:1844–1852. doi:
Preeclampsia is a leading cause of maternal morbidity and 10.1097/CCM.0b013e31828a3e24
4. Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe
mortality worldwide, whose only definitive treatment—de-
obstetric morbidity in the United States. Obstet Gynecol. 2009;113:1299–
livery of the fetus and placenta—carries significant morbidity 1306. doi: 10.1097/AOG.0b013e3181a45b25
Downloaded from http://ahajournals.org by on April 15, 2019

and mortality for the neonate. Though the mortality of pre- 5. Goel A, Maski MR, Bajracharya S, Wenger JB, Zhang D, Salahuddin
eclampsia-eclampsia has decreased significantly in the United S, Shahul SS, Thadhani R, Seely EW, Karumanchi SA, Rana S.
Epidemiology and mechanisms of de novo and persistent hyperten-
States because of increased antenatal surveillance and early sion in the postpartum period. Circulation. 2015;132:1726–1733. doi:
interventions, the postpartum and lifelong sequelae of pree- 10.1161/CIRCULATIONAHA.115.015721
clampsia have risen in number and significance. Whether the 6. Bernstein PS, Martin JN Jr, Barton JR, Shields LE, Druzin ML, Scavone
risk predates and confounds preeclampsia or is a result thereof, BM, Frost J, Morton CH, Ruhl C, Slager J, Tsigas EZ, Jaffer S, Menard
MK. National partnership for maternal safety: consensus bundle on se-
we now know that women with a history of preeclampsia are vere hypertension during pregnancy and the postpartum period. Obstet
at increased risk for CVD250,263 and dementia258 later in life, Gynecol. 2017;130:347–357. doi: 10.1097/AOG.0000000000002115
including acutely fatal myocardial infarction without the pro- 7. Coutinho T, Lamai O, Nerenberg K. Hypertensive disorders of preg-
nancy and cardiovascular diseases: current knowledge and future
gressive, forewarning symptoms of the acute coronary syn-
directions. Curr Treat Options Cardiovasc Med. 2018;20:56. doi:
drome.263 An increased focus on interventional studies during 10.1007/s11936-018-0653-8
the postpartum, asymptomatic phase is imperative to mini- 8. Tooher J, Thornton C, Makris A, Ogle R, Korda A, Hennessy A.
mize the risk of CVD and its potentially fatal complications. All hypertensive disorders of pregnancy increase the risk of fu-
ture cardiovascular disease. Hypertension. 2017;70:798–803. doi:
Improved risk stratification and therapeutics are other areas 10.1161/HYPERTENSIONAHA.117.09246
of opportunity with several innovations on the horizon. While 9. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Pre-eclampsia
ongoing work in placental oxidative stress and the maternal Identification Group. Clinical risk factors for pre-eclampsia determined
immune response demonstrate intriguing insights, perhaps in early pregnancy: systematic review and meta-analysis of large cohort
studies. BMJ. 2016;353:i1753. doi: 10.1136/bmj.i1753
the most promising area under investigation is the maternal 10. Boyd PA, Lindenbaum RH, Redman C. Pre-eclampsia and trisomy 13: a
angiogenic factor imbalance and its effects on vascular func- possible association. Lancet. 1987;2:425–427.
tion. Ongoing development of methods of risk stratification 11. Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor
for pre-eclampsia in primigravidas. Int J Gynaecol Obstet. 1998;60:23–27.
using ratios of proangiogenic factors—such as PlGF—and an- 12. Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fe-
tiangiogenic factors—such as sFLT1 and sENG—have high tal genetic factors account for most of familial aggregation of pree-
detection rates for preterm preeclampsia when incorporated clampsia: a population-based Swedish cohort study. Am J Med Genet A.
into algorithms with other predictive elements264 and have 2004;130A:365–371. doi: 10.1002/ajmg.a.30257
13. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo

shown high negative predictive value as an isolated assay. J, Varner MW. Paternal and maternal components of the predis-
Removal of antiangiogenic proteins through plasma apheresis position to preeclampsia. N Engl J Med. 2001;344:867–872. doi:
significantly prolongs gestation compared with controls and 10.1056/NEJM200103223441201
14. McGinnis R, Steinthorsdottir V, Williams NO, et al; FINNPEC

attenuates the symptoms of preeclampsia,232,233 and recombi-
Consortium; GOPEC Consortium. Variants in the fetal genome near FLT1
nant human PlGF and siRNA have shown promising results are associated with risk of preeclampsia. Nat Genet. 2017;49:1255–1260.
in animal models,234,235,237 suggesting possible therapeutic doi: 10.1038/ng.3895
1106  Circulation Research  March 29, 2019

15. Gray KJ, Kovacheva VP, Mirzakhani H, et al. Gene-centric analysis of 38. Burton GJ, Hempstock J, Jauniaux E. Nutrition of the human fetus dur-
preeclampsia identifies maternal association at PLEKHG1. Hypertension. ing the first trimester–a review. Placenta. 2001;22(suppl A):S70–S77. doi:
2018;72:408–416. doi: 10.1161/HYPERTENSIONAHA.117.10688 10.1053/plac.2001.0639
16. Morgan MA, Thurnau GR. Pregnancy-induced hypertension without pro- 39. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ.
teinuria: is it true preeclampsia? South Med J. 1988;81:210–213. Onset of maternal arterial blood flow and placental oxidative stress.
17. Barton JR, O’brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild ges- A possible factor in human early pregnancy failure. Am J Pathol.
tational hypertension remote from term: progression and outcome. Am J 2000;157:2111–2122. doi: 10.1016/S0002-9440(10)64849-3
Obstet Gynecol. 2001;184:979–983. doi: 10.1067/mob.2001.112905 40. Rajakumar A, Brandon HM, Daftary A, Ness R, Conrad KP. Evidence
18. ACOG practice bulletin no. 202 summary: gestational hypertension and for the functional activity of hypoxia-inducible transcription factors over-
preeclampsia. Obstet Gynecol. 2019;133:211–214. expressed in preeclamptic placentae. Placenta. 2004;25:763–769. doi:
19. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. 10.1016/j.placenta.2004.02.011
Science. 2005;308:1592–1594. doi: 10.1126/science.1111726 41. Tal R, Shaish A, Barshack I, Polak-Charcon S, Afek A, Volkov A, Feldman
20. Romero R, Chaiworapongsa T. Preeclampsia: a link between trophoblast B, Avivi C, Harats D. Effects of hypoxia-inducible factor-1alpha overex-
dysregulation and an antiangiogenic state. J Clin Invest. 2013;123:2775– pression in pregnant mice: possible implications for preeclampsia and
2777. doi: 10.1172/JCI70431 intrauterine growth restriction. Am J Pathol. 2010;177:2950–2962. doi:
21. Palei AC, Spradley FT, Warrington JP, George EM, Granger JP.
10.2353/ajpath.2010.090800
Pathophysiology of hypertension in pre-eclampsia: a lesson in in- 42. Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski
tegrative physiology. Acta Physiol (Oxf). 2013;208:224–233. doi: M, Post M. Hypoxia-inducible factor-1 mediates the biological effects of
10.1111/apha.12106 oxygen on human trophoblast differentiation through TGFbeta(3). J Clin
22. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin Invest. 2000;105:577–587. doi: 10.1172/JCI8316
MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 43. Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S,
1989;161:1200–1204. Augustin HG, Gattone VH, Folkman J, Strauss JF, Kalluri R. Deficiency in
23. Brosens I, Robertson WB, Dixon HG. The physiological response of catechol-O-methyltransferase and 2-methoxyoestradiol is associated with
the vessels of the placental bed to normal pregnancy. J Pathol Bacteriol. pre-eclampsia. Nature. 2008;453:1117–1121. doi: 10.1038/nature06951
1967;93:569–579. doi: 10.1002/path.1700930218 44. Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view.
24. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Placenta. 2009;30(suppl A):S38–S42. doi: 10.1016/j.placenta.2008.11.021
Syndromes” are associated with disorders of deep placentation. Am J 45. Derwig I, Lythgoe DJ, Barker GJ, Poon L, Gowland P, Yeung R, Zelaya
Obstet Gynecol. 2011;204:193–201. doi: 10.1016/j.ajog.2010.08.009 F, Nicolaides K. Association of placental perfusion, as assessed by mag-
25. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure netic resonance imaging and uterine artery Doppler ultrasound, and its
of human cytotrophoblasts to mimic a vascular adhesion phenotype. One relationship to pregnancy outcome. Placenta. 2013;34:885–891. doi:
cause of defective endovascular invasion in this syndrome? J Clin Invest. 10.1016/j.placenta.2013.07.006
1997;99:2152–2164. doi: 10.1172/JCI119388 46. Sohlberg S, Mulic-Lutvica A, Lindgren P, Ortiz-Nieto F, Wikström

26. Brosens I, Renaer M. On the pathogenesis of placental infarcts in pre- AK, Wikström J. Placental perfusion in normal pregnancy and early
eclampsia. J Obstet Gynaecol Br Commonw. 1972;79:794–799. and late preeclampsia: a magnetic resonance imaging study. Placenta.
27. De Wolf F, Robertson WB, Brosens I. The ultrastructure of acute atherosis 2014;35:202–206. doi: 10.1016/j.placenta.2014.01.008
in hypertensive pregnancy. Am J Obstet Gynecol. 1975;123:164–174. 47. Sohlberg S, Mulic-Lutvica A, Olovsson M, Weis J, Axelsson O, Wikström
28. Lin S, Shimizu I, Suehara N, Nakayama M, Aono T. Uterine artery J, Wikström AK. Magnetic resonance imaging-estimated placental perfu-
Downloaded from http://ahajournals.org by on April 15, 2019

Doppler velocimetry in relation to trophoblast migration into the myome- sion in fetal growth assessment. Ultrasound Obstet Gynecol. 2015;46:700–
trium of the placental bed. Obstet Gynecol. 1995;85:760–765. 705. doi: 10.1002/uog.14786
29. North RA, Ferrier C, Long D, Townend K, Kincaid-Smith P. Uterine 48. Sørensen A, Peters D, Fründ E, Lingman G, Christiansen O, Uldbjerg
artery Doppler flow velocity waveforms in the second trimester for the N. Changes in human placental oxygenation during maternal hyperoxia
prediction of preeclampsia and fetal growth retardation. Obstet Gynecol. estimated by blood oxygen level-dependent magnetic resonance imag-
1994;83:378–386. ing (BOLD MRI). Ultrasound Obstet Gynecol. 2013;42:310–314. doi:
30. Hecht JL, Zsengeller ZK, Spiel M, Karumanchi SA, Rosen S. Revisiting 10.1002/uog.12395
decidual vasculopathy. Placenta. 2016;42:37–43. doi: 10.1016/j.placenta. 49. Sinding M, Peters DA, Poulsen SS, Frøkjær JB, Christiansen OB,

2016.04.006 Petersen A, Uldbjerg N, Sørensen A. Placental baseline conditions mod-
31. Stanek J. Histological features of shallow placental implantation unify ear- ulate the hyperoxic BOLD-MRI response. Placenta. 2018;61:17–23. doi:
ly-onset and late-onset preeclampsia [published online October 9, 2018]. 10.1016/j.placenta.2017.11.002
Pediatr Dev Pathol. doi: 10.1177/1093526618803759 50. Luo J, Abaci Turk E, Bibbo C, et al. In vivo quantification of placental
32. Stevens DU, Al-Nasiry S, Bulten J, Spaanderman ME. Decidual vascu- insufficiency by BOLD MRI: a human study. Sci Rep. 2017;7:3713. doi:
lopathy in preeclampsia: lesion characteristics relate to disease sever- 10.1038/s41598-017-03450-0
ity and perinatal outcome. Placenta. 2013;34:805–809. doi: 10.1016/j. 51. Many A, Hubel CA, Fisher SJ, Roberts JM, Zhou Y. Invasive cytotropho-
placenta.2013.05.008 blasts manifest evidence of oxidative stress in preeclampsia. Am J Pathol.
33. Rabaglino MB, Post Uiterweer ED, Jeyabalan A, Hogge WA, Conrad KP. 2000;156:321–331. doi: 10.1016/S0002-9440(10)64733-5
Bioinformatics approach reveals evidence for impaired endometrial matu- 52. Zhuang B, Luo X, Rao H, Li Q, Shan N, Liu X, Qi H. Oxidative

ration before and during early pregnancy in women who developed pree- stress-induced C/EBPβ inhibits β-catenin signaling molecule involv-
clampsia. Hypertension. 2015;65:421–429. ing in the pathology of preeclampsia. Placenta. 2015;36:839–846. doi:
34. Garrido-Gomez T, Dominguez F, Quiñonero A, Diaz-Gimeno P, Kapidzic 10.1016/j.placenta.2015.06.016
M, Gormley M, Ona K, Padilla-Iserte P, McMaster M, Genbacev O, 53. Huang QT, Wang SS, Zhang M, Huang LP, Tian JW, Yu YH, Wang ZJ,
Perales A, Fisher SJ, Simón C. Defective decidualization during and Zhong M. Advanced oxidation protein products enhances soluble Fms-
after severe preeclampsia reveals a possible maternal contribution to like tyrosine kinase 1 expression in trophoblasts: a possible link between
the etiology. Proc Natl Acad Sci USA. 2017;114:E8468–E8477. doi: oxidative stress and preeclampsia. Placenta. 2013;34:949–952. doi:
10.1073/pnas.1706546114 10.1016/j.placenta.2013.06.308
35. Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA. A role 54. Vaughan JE, Walsh SW. Oxidative stress reproduces placental abnor-
for menstruation in preconditioning the uterus for successful pregnancy. malities of preeclampsia. Hypertens Pregnancy. 2002;21:205–223. doi:
Am J Obstet Gynecol. 2009;200:615.e1–615.e6. doi: 10.1016/j.ajog. 10.1081/PRG-120015848
2008.11.037 55. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH; Vitamins in Pre-
36. Gray KJ, Saxena R, Karumanchi SA. Genetic predisposition to pree- eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant
clampsia is conferred by fetal DNA variants near FLT1, a gene involved in women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled
the regulation of angiogenesis. Am J Obstet Gynecol. 2018;218:211–218. trial. Lancet. 2006;367:1145–1154. doi: 10.1016/S0140-6736(06)68433-X
doi: 10.1016/j.ajog.2017.11.562 56. Roberts JM, Myatt L, Spong CY, et al; Eunice Kennedy Shriver National
37. Soleymanlou N, Jurisica I, Nevo O, Ietta F, Zhang X, Zamudio S, Post Institute of Child Health and Human Development Maternal-Fetal
M, Caniggia I. Molecular evidence of placental hypoxia in preeclamp- Medicine Units Network. Vitamins C and E to prevent complications of
sia. J Clin Endocrinol Metab. 2005;90:4299–4308. doi: 10.1210/jc. pregnancy-associated hypertension. N Engl J Med. 2010;362:1282–1291.
2005-0078 doi: 10.1056/NEJMoa0908056
Rana et al   Preeclampsia and Vascular Disease   1107

57. Zsengellér ZK, Rajakumar A, Hunter JT, Salahuddin S, Rana S, Stillman induced hypertension. Hypertension. 2011;57:941–948. doi: 10.1161/
IE, Ananth Karumanchi S. Trophoblast mitochondrial function is impaired HYPERTENSIONAHA.111.169755
in preeclampsia and correlates negatively with the expression of soluble 75. Cui Y, Wang W, Dong N, et al. Role of corin in trophoblast invasion and
fms-like tyrosine kinase 1. Pregnancy Hypertens. 2016;6:313–319. doi: uterine spiral artery remodelling in pregnancy. Nature. 2012;484:246–250.
10.1016/j.preghy.2016.06.004 doi: 10.1038/nature10897
58. Kai S, Tanaka T, Daijo H, Harada H, Kishimoto S, Suzuki K, Takabuchi S, 76. Gu Y, Thompson D, Xu J, Lewis DF, Morgan JA, Cooper DB,

Takenaga K, Fukuda K, Hirota K. Hydrogen sulfide inhibits hypoxia- but McCathran CE, Wang Y. Aberrant pro-atrial natriuretic peptide/corin/
not anoxia-induced hypoxia-inducible factor 1 activation in a von hippel- natriuretic peptide receptor signaling is present in maternal vascular en-
lindau- and mitochondria-dependent manner. Antioxid Redox Signal. dothelium in preeclampsia. Pregnancy Hypertens. 2018;11:1–6. doi:
2012;16:203–216. doi: 10.1089/ars.2011.3882 10.1016/j.preghy.2017.12.001
59. Covarrubias AE, Lecarpentier E, Lo A, Salahuddin S, Gray KJ, Karumanchi 77. Miyazaki J, Nishizawa H, Kambayashi A, Ito M, Noda Y, Terasawa

SA, Zsengeller ZK. AP39, a modulator of mitochondrial bioenergetics, S, Kato T, Miyamura H, Shiogama K, Sekiya T, Kurahashi H, Fujii T.
reduces anti-angiogenic response and oxidative stress in hypoxia-ex- Increased levels of soluble corin in pre-eclampsia and fetal growth restric-
posed trophoblasts: relevance for preeclampsia pathogenesis. Am J Pathol. tion. Placenta. 2016;48:20–25. doi: 10.1016/j.placenta.2016.10.002
2019;189:104–114. 78. Barnea ER, MacLusky NJ, DeCherney AH, Naftolin F. Catechol-o-

60. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, methyl transferase activity in the human term placenta. Am J Perinatol.
Rodriguez AM, Schumacker PT. Reactive oxygen species generated at 1988;5:121–127. doi: 10.1055/s-2007-999669
mitochondrial complex III stabilize hypoxia-inducible factor-1alpha dur- 79. Berg D, Sonsalla R, Kuss E. Concentrations of 2-methoxyoestrogens
ing hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000;275:25130– in human serum measured by a heterologous immunoassay with an
25138. doi: 10.1074/jbc.M001914200 125I-labelled ligand. Acta Endocrinol (Copenh). 1983;103:282–288.
61. Vaka VR, McMaster KM, Cunningham MW Jr, Ibrahim T, Hazlewood R, 80. Palmer K, Saglam B, Whitehead C, Stock O, Lappas M, Tong S. Severe
Usry N, Cornelius DC, Amaral LM, LaMarca B. Role of mitochondrial dys- early-onset preeclampsia is not associated with a change in placen-
function and reactive oxygen species in mediating hypertension in the re- tal catechol O-methyltransferase (COMT) expression. Am J Pathol.
duced uterine perfusion pressure rat model of preeclampsia. Hypertension. 2011;178:2484–2488. doi: 10.1016/j.ajpath.2011.02.029
2018;72:703–711. doi: 10.1161/HYPERTENSIONAHA.118.11290 81. Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int
62. Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones J Dev Biol. 2010;54:281–294. doi: 10.1387/ijdb.082763jb
DS, Burton GJ. Evidence of placental translation inhibition and endoplas- 82. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F,
mic reticulum stress in the etiology of human intrauterine growth restric- Masch R, Lockwood CJ, Schachter AD, Park PJ, Strominger JL. Human de-
tion. Am J Pathol. 2008;173:451–462. doi: 10.2353/ajpath.2008.071193 cidual natural killer cells are a unique NK cell subset with immunomodula-
63. Yung HW, Korolchuk S, Tolkovsky AM, Charnock-Jones DS, Burton tory potential. J Exp Med. 2003;198:1201–1212. doi: 10.1084/jem.20030305
GJ. Endoplasmic reticulum stress exacerbates ischemia-reperfu- 83. Moffett A, Colucci F. Uterine NK cells: active regulators at the maternal-
sion-induced apoptosis through attenuation of Akt protein synthe- fetal interface. J Clin Invest. 2014;124:1872–1879. doi: 10.1172/JCI68107
sis in human choriocarcinoma cells. FASEB J. 2007;21:872–884. doi: 84. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol.
10.1096/fj.06-6054com 2002;2:656–663. doi: 10.1038/nri886
64. Lian IA, Løset M, Mundal SB, Fenstad MH, Johnson MP, Eide IP, Bjørge 85. Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, Robson
L, Freed KA, Moses EK, Austgulen R. Increased endoplasmic reticulum SC, Bulmer JN. Expression of angiogenic growth factors by uterine nat-
stress in decidual tissue from pregnancies complicated by fetal growth ural killer cells during early pregnancy. J Leukoc Biol. 2006;80:572–580.
Downloaded from http://ahajournals.org by on April 15, 2019

restriction with and without pre-eclampsia. Placenta. 2011;32:823–829. doi: 10.1189/jlb.0406250


doi: 10.1016/j.placenta.2011.08.005 86. Parham P, Moffett A. Variable NK cell receptors and their MHC class I li-
65. Fu J, Zhao L, Wang L, Zhu X. Expression of markers of endoplasmic re- gands in immunity, reproduction and human evolution. Nat Rev Immunol.
ticulum stress-induced apoptosis in the placenta of women with early and 2013;13:133–144. doi: 10.1038/nri3370
late onset severe pre-eclampsia. Taiwan J Obstet Gynecol. 2015;54:19–23. 87. Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moffett A. Human
doi: 10.1016/j.tjog.2014.11.002 leucocyte antigen (HLA) expression of primary trophoblast cells and pla-
66. Du L, He F, Kuang L, Tang W, Li Y, Chen D. eNOS/iNOS and endoplasmic cental cell lines, determined using single antigen beads to characterize
reticulum stress-induced apoptosis in the placentas of patients with pree- allotype specificities of anti-HLA antibodies. Immunology. 2009;127:26–
clampsia. J Hum Hypertens. 2017;31:49–55. doi: 10.1038/jhh.2016.17 39. doi: 10.1111/j.1365-2567.2008.03019.x
67. Mizuuchi M, Cindrova-Davies T, Olovsson M, Charnock-Jones DS,
88. Madeja Z, Yadi H, Apps R, Boulenouar S, Roper SJ, Gardner L, Moffett A,
Burton GJ, Yung HW. Placental endoplasmic reticulum stress negatively Colucci F, Hemberger M. Paternal MHC expression on mouse trophoblast
regulates transcription of placental growth factor via ATF4 and ATF6β: affects uterine vascularization and fetal growth. Proc Natl Acad Sci USA.
implications for the pathophysiology of human pregnancy complications. 2011;108:4012–4017. doi: 10.1073/pnas.1005342108
J Pathol. 2016;238:550–561. doi: 10.1002/path.4678 89. Kieckbusch J, Gaynor LM, Moffett A, Colucci F. MHC-dependent inhi-
68. George EM, Granger JP. Heme oxygenase in pregnancy and preeclamp- bition of uterine NK cells impedes fetal growth and decidual vascular re-
sia. Curr Opin Nephrol Hypertens. 2013;22:156–162. doi: 10.1097/MNH. modelling. Nat Commun. 2014;5:3359. doi: 10.1038/ncomms4359
0b013e32835d19f7 90. Hiby SE, Walker JJ, O’shaughnessy KM, Redman CW, Carrington M,
69. Cudmore M, Ahmad S, Al-Ani B, Fujisawa T, Coxall H, Chudasama K, Devey Trowsdale J, Moffett A. Combinations of maternal KIR and fetal HLA-C
LR, Wigmore SJ, Abbas A, Hewett PW, Ahmed A. Negative regulation of sol- genes influence the risk of preeclampsia and reproductive success. J Exp
uble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. Med. 2004;200:957–965. doi: 10.1084/jem.20041214
2007;115:1789–1797. doi: 10.1161/CIRCULATIONAHA.106.660134 91. Hiby SE, Apps R, Sharkey AM, et al. Maternal activating KIRs protect
70. George EM, Colson D, Dixon J, Palei AC, Granger JP. Heme oxygen- against human reproductive failure mediated by fetal HLA-C2. J Clin
ase-1 attenuates hypoxia-induced sFlt-1 and oxidative stress in placental Invest. 2010;120:4102–4110. doi: 10.1172/JCI43998
villi through its metabolic products CO and bilirubin. Int J Hypertens. 92. Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A. Association
2012;2012:486053. doi: 10.1155/2012/486053 of maternal killer-cell immunoglobulin-like receptors and parental HLA-C
71. Origassa CS, Câmara NO. Cytoprotective role of heme oxygenase-1 and genotypes with recurrent miscarriage. Hum Reprod. 2008;23:972–976.
heme degradation derived end products in liver injury. World J Hepatol. doi: 10.1093/humrep/den011
2013;5:541–549. doi: 10.4254/wjh.v5.i10.541 93. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial

72. McCaig D, Lyall F. Inhibitors of heme oxygenase reduce invasion of hu- growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res.
man primary cytotrophoblast cells in vitro. Placenta. 2009;30:536–538. 2004;95:884–891. doi: 10.1161/01.RES.0000147365.86159.f5
doi: 10.1016/j.placenta.2009.03.004 94. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA,
73. Bilban M, Haslinger P, Prast J, Klinglmüller F, Woelfel T, Haider S, Sachs Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi
A, Otterbein LE, Desoye G, Hiden U, Wagner O, Knöfler M. Identification SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may con-
of novel trophoblast invasion-related genes: heme oxygenase-1 con- tribute to endothelial dysfunction, hypertension, and proteinuria in pree-
trols motility via peroxisome proliferator-activated receptor gamma. clampsia. J Clin Invest. 2003;111:649–658. doi: 10.1172/JCI17189
Endocrinology. 2009;150:1000–1013. doi: 10.1210/en.2008-0456 95. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth
74. George EM, Cockrell K, Aranay M, Csongradi E, Stec DE, Granger factor activity by an endogenously encoded soluble receptor. Proc Natl
JP. Induction of heme oxygenase 1 attenuates placental ischemia- Acad Sci USA. 1993;90:10705–10709.
1108  Circulation Research  March 29, 2019

96. Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W. Collaboration. Accuracy of circulating placental growth factor, vas-
Vascular endothelial growth factor induces endothelial fenestrations in cular endothelial growth factor, soluble fms-like tyrosine kinase
vitro. J Cell Biol. 1998;140:947–959. 1 and soluble endoglin in the prediction of pre-eclampsia: a sys-
97. De Falco S. The discovery of placenta growth factor and its biological tematic review and meta-analysis. BJOG. 2012;119:778–787. doi:
activity. Exp Mol Med. 2012;44:1–9. doi: 10.3858/emm.2012.44.1.025 10.1111/j.1471-0528.2012.03311.x
98. Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda 113. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-
S, Yano T, Tsutsumi O, Taketani Y. Elevated serum soluble vascular en- trimester prediction of hypertensive disorders in pregnancy. Hypertension.
dothelial growth factor receptor 1 (sVEGFR-1) levels in women with 2009;53:812–818. doi: 10.1161/HYPERTENSIONAHA.108.127977
preeclampsia. J Clin Endocrinol Metab. 2003;88:2348–2351. doi: 114. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the
10.1210/jc.2002-021942 maternal endothelium: the role of antiangiogenic factors and implica-
99. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, tions for later cardiovascular disease. Circulation. 2011;123:2856–2869.
Schaaps JP, Cabrol D, Frankenne F, Foidart JM. Overexpression of doi: 10.1161/CIRCULATIONAHA.109.853127
the soluble vascular endothelial growth factor receptor in preeclamptic 115. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai

patients: pathophysiological consequences. J Clin Endocrinol Metab. BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP
2003;88:5555–5563. doi: 10.1210/jc.2003-030528 Study Group. Soluble endoglin and other circulating antiangiogenic
100. Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD, Hankins factors in preeclampsia. N Engl J Med. 2006;355:992–1005. doi:
GD, Saade GR. The effect of over-expression of sFlt-1 on blood pres- 10.1056/NEJMoa055352
sure and the occurrence of other manifestations of preeclampsia in unre- 116. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes
strained conscious pregnant mice. Am J Obstet Gynecol. 2007;196:396. to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–649. doi:
e1–396.e7; discussion 396.e7. doi: 10.1016/j.ajog.2006.12.024 10.1038/nm1429
101. Launay-Vacher V, Deray G. Hypertension and proteinuria: a class-effect 117. Wallace K, Morris R, Kyle PB, Cornelius D, Darby M, Scott J, Moseley
of antiangiogenic therapies. Anticancer Drugs. 2009;20:81–82. doi: J, Chatman K, Lamarca B. Hypertension, inflammation and T lym-
10.1097/CAD.0b013e3283161012 phocytes are increased in a rat model of HELLP syndrome. Hypertens
102. Vigneau C, Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Pregnancy. 2014;33:41–54. doi: 10.3109/10641955.2013.835820
Laguerre B, Verhoest G, Goujon JM, Belaud-Rotureau MA, Rioux- 118. Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado
Leclercq N. All anti-vascular endothelial growth factor drugs can induce AE, Himes NC, Matharu KS, Karumanchi SA, D’Amore PA. VEGF and
‘pre-eclampsia-like syndrome’: a RARe study. Nephrol Dial Transplant. TGF-beta are required for the maintenance of the choroid plexus and ep-
2014;29:325–332. doi: 10.1093/ndt/gft465 endyma. J Exp Med. 2008;205:491–501. doi: 10.1084/jem.20072041
103. Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P,
119. Wallace K, Bean C, Bowles T, Spencer SK, Randle W, Kyle PB,

Lindenmaier W, Christofori G, Gross V, Gonzalves ACh, Gröne HJ, Shaffery J. Hypertension, anxiety, and blood-brain barrier permeability
Ahmed A, Weich HA. Reduction of circulating soluble Flt-1 allevi- are increased in postpartum severe preeclampsia/hemolysis, elevated
ates preeclampsia-like symptoms in a mouse model. J Cell Mol Med. liver enzymes, and low platelet count syndrome rats. Hypertension.
2010;14:1857–1867. doi: 10.1111/j.1582-4934.2009.00820.x 2018;72:946–954. doi: 10.1161/HYPERTENSIONAHA.118.11770
104. Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka Y, 120. Askelund KJ, Chamley LW. Trophoblast deportation part I: review

Takakura N, Kimura T, Okabe M. Pravastatin induces placental growth of the evidence demonstrating trophoblast shedding and deporta-
factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl tion during human pregnancy. Placenta. 2011;32:716–723. doi:
Acad Sci USA. 2011;108:1451–1455. doi: 10.1073/pnas.1011293108 10.1016/j.placenta.2011.07.081
Downloaded from http://ahajournals.org by on April 15, 2019

105. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, 121. Pantham P, Askelund KJ, Chamley LW. Trophoblast deportation part
O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, II: a review of the maternal consequences of trophoblast deportation.
Protter AA, Pollitt NS. Recombinant vascular endothelial growth fac- Placenta. 2011;32:724–731. doi: 10.1016/j.placenta.2011.06.019
tor 121 attenuates hypertension and improves kidney damage in a 122. Attwood HD, Park WW. Embolism to the lungs by trophoblast. J Obstet
rat model of preeclampsia. Hypertension. 2007;50:686–692. doi: Gynaecol Br Commonw. 1961;68:611–617.
10.1161/HYPERTENSIONAHA.107.092098 123. Knight M, Redman CW, Linton EA, Sargent IL. Shedding of syncytiotro-
106. Hladunewich MA, Steinberg G, Karumanchi SA, Levine RJ, Keating phoblast microvilli into the maternal circulation in pre-eclamptic preg-
S, Kingdom J, Keunen J. Angiogenic factor abnormalities and fetal nancies. Br J Obstet Gynaecol. 1998;105:632–640.
demise in a twin pregnancy. Nat Rev Nephrol. 2009;5:658–662. doi: 124. Germain SJ, Sacks GP, Sooranna SR, Soorana SR, Sargent IL, Redman
10.1038/nrneph.2009.154 CW. Systemic inflammatory priming in normal pregnancy and pree-
107. Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with par- clampsia: the role of circulating syncytiotrophoblast microparticles. J
vovirus-induced hydrops. N Engl J Med. 2006;354:1857–1858. doi: Immunol. 2007;178:5949–5956.
10.1056/NEJMc052721 125. Guller S, Tang Z, Ma YY, Di Santo S, Sager R, Schneider H. Protein
108. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
composition of microparticles shed from human placenta during pla-
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, cental perfusion: Potential role in angiogenesis and fibrinolysis in pree-
Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and clampsia. Placenta. 2011;32:63–69. doi: 10.1016/j.placenta.2010.10.011
the risk of preeclampsia. N Engl J Med. 2004;350:672–683. doi: 126. Chang X, Yao J, He Q, Liu M, Duan T, Wang K. Exosomes from
10.1056/NEJMoa031884 women with preeclampsia induced vascular dysfunction by deliver-
109. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, ing sFlt (Soluble Fms-Like Tyrosine Kinase)-1 and sEng (Soluble
Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa Endoglin) to endothelial cells. Hypertension. 2018;72:1381–1390. doi:
T, Levine RJ, Karumanchi SA. A longitudinal study of angiogenic (pla- 10.1161/HYPERTENSIONAHA.118.11706
cental growth factor) and anti-angiogenic (soluble endoglin and soluble 127. Southcombe J, Tannetta D, Redman C, Sargent I. The immunomodulatory
vascular endothelial growth factor receptor-1) factors in normal preg- role of syncytiotrophoblast microvesicles. PLoS One. 2011;6:e20245.
nancy and patients destined to develop preeclampsia and deliver a small doi: 10.1371/journal.pone.0020245
for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21:9– 128. Gupta AK, Rusterholz C, Huppertz B, Malek A, Schneider H, Holzgreve
23. doi: 10.1080/14767050701830480 W, Hahn S. A comparative study of the effect of three different syncytio-
110. Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH,
trophoblast micro-particles preparations on endothelial cells. Placenta.
Levine RJ, Lim KH, Wenger JB, Thadhani R, Karumanchi SA. 2005;26:59–66. doi: 10.1016/j.placenta.2004.04.004
Angiogenic factors and the risk of adverse outcomes in women 129. O’Brien M, Baczyk D, Kingdom JC. Endothelial dysfunction in severe
with suspected preeclampsia. Circulation. 2012;125:911–919. doi: preeclampsia is mediated by soluble factors, rather than extracellular
10.1161/CIRCULATIONAHA.111.054361 vesicles. Sci Rep. 2017;7:5887. doi: 10.1038/s41598-017-06178-z
111. Rana S, Schnettler WT, Powe C, Wenger J, Salahuddin S, Cerdeira AS, 130. Harmon A, Cornelius D, Amaral L, Paige A, Herse F, Ibrahim T,

Verlohren S, Perschel FH, Arany Z, Lim KH, Thadhani R, Karumanchi Wallukat G, Faulkner J, Moseley J, Dechend R, LaMarca B. IL-10 sup-
SA. Clinical characterization and outcomes of preeclampsia with normal plementation increases Tregs and decreases hypertension in the RUPP
angiogenic profile. Hypertens Pregnancy. 2013;32:189–201. doi: rat model of preeclampsia. Hypertens Pregnancy. 2015;34:291–306. doi:
10.3109/10641955.2013.784788 10.3109/10641955.2015.1032054
112. Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van 131. Weel IC, Baergen RN, Romão-Veiga M, Borges VT, Ribeiro VR, Witkin
der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT SS, Bannwart-Castro C, Peraçoli JC, De Oliveira L, Peraçoli MT.
Rana et al   Preeclampsia and Vascular Disease   1109

Association between placental lesions, cytokines and angiogenic factors atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomer-
in pregnant women with preeclampsia. PLoS One. 2016;11:e0157584. ulonephritis, and the HELLP syndrome. Blood. 2008;111:624–632. doi:
doi: 10.1371/journal.pone.0157584 10.1182/blood-2007-04-084533
132. Xu J, Gu Y, Sun J, Zhu H, Lewis DF, Wang Y. Reduced CD200 expres- 150. Kavanagh D, Richards A, Atkinson J. Complement regulatory genes and
sion is associated with altered Th1/Th2 cytokine production in placental hemolytic uremic syndromes. Annu Rev Med. 2008;59:293–309. doi:
trophoblasts from preeclampsia. Am J Reprod Immunol. 2018;79:1. doi: 10.1146/annurev.med.59.060106.185110
10.1111/aji.12763 151. Zipfel PF, Misselwitz J, Licht C, Skerka C. The role of defective com-
133. Peixoto AB, Araujo Júnior E, Ribeiro JU, Rodrigues DB, Castro
plement control in hemolytic uremic syndrome. Semin Thromb Hemost.
EC, Caldas TM, Rodrigues Júnior V. Evaluation of inflammatory 2006;32:146–154. doi: 10.1055/s-2006-939770
mediators in the deciduas of pregnant women with pre-eclampsia/ 152. Zipfel PF, Skerka C. Complement dysfunction in hemolytic

eclampsia. J Matern Fetal Neonatal Med. 2016;29:75–79. doi: uremic syndrome. Curr Opin Rheumatol. 2006;18:548–555. doi:
10.3109/14767058.2014.987117 10.1097/01.bor.0000240370.47336.ae
134. Darmochwal-Kolarz D, Rolinski J, Leszczynska-Goarzelak B, Oleszczuk 153. Burwick RM, Feinberg BB. Eculizumab for the treatment of pre-

J. The expressions of intracellular cytokines in the lymphocytes of pree- eclampsia/HELLP syndrome. Placenta. 2013;34:201–203. doi:
clamptic patients. Am J Reprod Immunol. 2002;48:381–386. 10.1016/j.placenta.2012.11.014
135. Chen W, Qian L, Wu F, Li M, Wang H. Significance of toll-
154. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor
like receptor 4 signaling in peripheral blood monocytes of pre- eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med.
eclamptic patients. Hypertens Pregnancy. 2015;34:486–494. doi: 2013;368:2169–2181. doi: 10.1056/NEJMoa1208981
10.3109/10641955.2015.1077860 155. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M,
136. Medeiros LT, Peraçoli JC, Bannwart-Castro CF, Romão M, Weel
Gaber AO, Menne J, Minetti EE, Provôt F, Rondeau E, Ruggenenti P,
IC, Golim MA, de Oliveira LG, Kurokawa CS, Medeiros Borges VT, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM. Terminal com-
Peraçoli MT. Monocytes from pregnant women with pre-eclampsia are plement inhibitor eculizumab in adult patients with atypical hemolytic
polarized to a M1 phenotype. Am J Reprod Immunol. 2014;72:5–13. doi: uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis.
10.1111/aji.12222 2016;68:84–93. doi: 10.1053/j.ajkd.2015.12.034
137. Campos-Cañas J, Romo-Palafox I, Albani-Campanario M, Hernández- 156. Demir E, Yazici H, Ozluk Y, Kilicaslan I, Turkmen A. Pregnant woman
Guerrero C. An imbalance in the production of proinflammatory and with atypical hemolytic uremic syndrome delivered a healthy newborn
anti-inflammatory cytokines is observed in whole blood cultures of under eculizumab treatment. Case Rep Nephrol Dial. 2016;6:143–148.
preeclamptic women in comparison with healthy pregnant women. doi: 10.1159/000454946
Hypertens Pregnancy. 2014;33:236–249. doi: 10.3109/10641955. 157. Gupta M, Feinberg BB, Burwick RM. Thrombotic microangiopathies of
2013.858744 pregnancy: differential diagnosis. Pregnancy Hypertens. 2018;12:29–34.
138. Cristofalo R, Bannwart-Castro CF, Magalhães CG, Borges VT, Peraçoli doi: 10.1016/j.preghy.2018.02.007
JC, Witkin SS, Peraçoli MT. Silibinin attenuates oxidative metabolism 158. Irani RA, Xia Y. The functional role of the renin-angiotensin system
and cytokine production by monocytes from preeclamptic women. Free in pregnancy and preeclampsia. Placenta. 2008;29:763–771. doi:
Radic Res. 2013;47:268–275. doi: 10.3109/10715762.2013.765951 10.1016/j.placenta.2008.06.011
139. Saito S, Sakai M. Th1/Th2 balance in preeclampsia. J Reprod Immunol. 159. Brown MA, Wang J, Whitworth JA. The renin-angiotensin-aldosterone
2003;59:161–173. system in pre-eclampsia. Clin Exp Hypertens. 1997;19:713–726. doi:
140. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cyto- 10.3109/10641969709083181
Downloaded from http://ahajournals.org by on April 15, 2019

kine interactions in the maternal-fetal relationship: is successful preg- 160. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of
nancy a TH2 phenomenon? Immunol Today. 1993;14:353–356. doi: angiotensin II pressor response throughout primigravid pregnancy. J Clin
10.1016/0167-5699(93)90235-D Invest. 1973;52:2682–2689. doi: 10.1172/JCI107462
141. Sowmya S, Sri Manjari K, Ramaiah A, Sunitha T, Nallari P, Jyothy A, 161. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jüpner
Venkateshwari A. Interleukin 10 gene promoter polymorphisms in women A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H,
with early-onset pre-eclampsia. Clin Exp Immunol. 2014;178:334–341. Luft FC. Patients with preeclampsia develop agonistic autoantibodies
doi: 10.1111/cei.12402 against the angiotensin AT1 receptor. J Clin Invest. 1999;103:945–952.
142. Regal JF, Burwick RM, Fleming SD. The complement system and
doi: 10.1172/JCI4106
preeclampsia. Curr Hypertens Rep. 2017;19:87. doi: 10.1007/ 162. Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, Hicks MJ, Ramin
s11906-017-0784-4 SM, Kellems RE, Xia Y. Angiotensin receptor agonistic autoantibodies
143. Derzsy Z, Prohászka Z, Rigó J Jr, Füst G, Molvarec A. Activation of induce pre-eclampsia in pregnant mice. Nat Med. 2008;14:855–862. doi:
the complement system in normal pregnancy and preeclampsia. Mol 10.1038/nm.1856
Immunol. 2010;47:1500–1506. doi: 10.1016/j.molimm.2010.01.021 163. LaMarca B, Parrish M, Ray LF, Murphy SR, Roberts L, Glover P,
144. Lokki AI, Kaartokallio T, Holmberg V, Onkamo P, Koskinen LLE,
Wallukat G, Wenzel K, Cockrell K, Martin JN Jr, Ryan MJ, Dechend R.
Saavalainen P, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Hypertension in response to autoantibodies to the angiotensin II type I
Villa PM, Hiltunen L, Laivuori H, Meri S. Analysis of complement receptor (AT1-AA) in pregnant rats: role of endothelin-1. Hypertension.
C3 gene reveals susceptibility to severe preeclampsia. Front Immunol. 2009;54:905–909. doi: 10.1161/HYPERTENSIONAHA.109.137935
2017;8:589. doi: 10.3389/fimmu.2017.00589 164. Yang X, Wang F, Lau WB, Zhang S, Zhang S, Liu H, Ma XL.

145. Gelber SE, Brent E, Redecha P, Perino G, Tomlinson S, Davisson
Autoantibodies isolated from preeclamptic patients induce endothe-
RL, Salmon JE. Prevention of defective placentation and pregnancy lial dysfunction via interaction with the angiotensin II AT1 receptor.
loss by blocking innate immune pathways in a syngeneic model Cardiovasc Toxicol. 2014;14:21–29. doi: 10.1007/s12012-013-9229-8
of placental insufficiency. J Immunol. 2015;195:1129–1138. doi: 165. Dechend R, Homuth V, Wallukat G, Kreuzer J, Park JK, Theuer J,
10.4049/jimmunol.1402220 Juepner A, Gulba DC, Mackman N, Haller H, Luft FC. AT(1) receptor
146. Qing X, Redecha PB, Burmeister MA, Tomlinson S, D’Agati VD,
agonistic antibodies from preeclamptic patients cause vascular cells to
Davisson RL, Salmon JE. Targeted inhibition of complement activation express tissue factor. Circulation. 2000;101:2382–2387.
prevents features of preeclampsia in mice. Kidney Int. 2011;79:331–339. 166. Xia Y, Wen H, Bobst S, Day MC, Kellems RE. Maternal autoantibod-
doi: 10.1038/ki.2010.393 ies from preeclamptic patients activate angiotensin receptors on human
147. Agostinis C, Bulla R, Tripodo C, Gismondi A, Stabile H, Bossi
trophoblast cells. J Soc Gynecol Investig. 2003;10:82–93.
F, Guarnotta C, Garlanda C, De Seta F, Spessotto P, Santoni A, 167. Dechend R, Viedt C, Müller DN, et al. AT1 receptor agonistic antibod-
Ghebrehiwet B, Girardi G, Tedesco F. An alternative role of C1q in ies from preeclamptic patients stimulate NADPH oxidase. Circulation.
cell migration and tissue remodeling: contribution to trophoblast inva- 2003;107:1632–1639. doi: 10.1161/01.CIR.0000058200.90059.B1
sion and placental development. J Immunol. 2010;185:4420–4429. doi: 168. LaMarca B, Wallukat G, Llinas M, Herse F, Dechend R, Granger JP.
10.4049/jimmunol.0903215 Autoantibodies to the angiotensin type I receptor in response to placental
148. Singh J, Ahmed A, Girardi G. Role of complement component C1q in ischemia and tumor necrosis factor alpha in pregnant rats. Hypertension.
the onset of preeclampsia in mice. Hypertension. 2011;58:716–724. doi: 2008;52:1168–1172. doi: 10.1161/HYPERTENSIONAHA.108.120576
10.1161/HYPERTENSIONAHA.111.175919 169. Parrish MR, Murphy SR, Rutland S, Wallace K, Wenzel K, Wallukat G,
149. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Keiser S, Ray LF, Dechend R, Martin JN, Granger JP, LaMarca B. The
Goodship TH, Atkinson JP. Membrane cofactor protein mutations in effect of immune factors, tumor necrosis factor-alpha, and agonistic
1110  Circulation Research  March 29, 2019

autoantibodies to the angiotensin II type I receptor on soluble fms-like tyro- esomeprazole is additive in reducing sFlt-1 secretion and decreasing en-
sine-1 and soluble endoglin production in response to hypertension during dothelial dysfunction - implications for treating preeclampsia. PLoS One.
pregnancy. Am J Hypertens. 2010;23:911–916. doi: 10.1038/ajh.2010.70 2018;13:e0188845. doi: 10.1371/journal.pone.0188845
170. Herse F, LaMarca B. Angiotensin II type 1 receptor autoantibody
191. Kalafat E, Sukur YE, Abdi A, Thilaganathan B, Khalil A. Metformin for
(AT1-AA)-mediated pregnancy hypertension. Am J Reprod Immunol. the prevention of hypertensive disorders of pregnancy in women with
2013;69:413–418. doi: 10.1111/aji.12072 gestational diabetes and obesity: a systematic review and meta-analysis.
171. Quitterer U, Fu X, Pohl A, Bayoumy KM, Langer A, AbdAlla S. Beta- Ultrasound Obstet Gynecol. 2018;52:706–714.
arrestin1 prevents preeclampsia by downregulation of mechanosensitive 192. Tangren JS, Wan Md Adnan WAH, Powe CE, Ecker J, Bramham K,
AT1-B2 receptor heteromers. Cell. 2019;176:318.e19–333.e19. doi: Hladunewich MA, Ankers E, Karumanchi SA, Thadhani R. Risk of
10.1016/j.cell.2018.10.050 preeclampsia and pregnancy complications in women with a his-
172. Zhou A, Carrell RW, Murphy MP, Wei Z, Yan Y, Stanley PL, Stein tory of acute kidney injury. Hypertension. 2018;72:451–459. doi:
PE, Broughton Pipkin F, Read RJ. A redox switch in angiotensino- 10.1161/HYPERTENSIONAHA.118.11161
gen modulates angiotensin release. Nature. 2010;468:108–111. doi: 193. Committee opinion no. 638: first-trimester risk assessment for early-
10.1038/nature09505 onset preeclampsia. Obstet Gynecol. 2015;126:e25–e27.
173. Burke SD, Zsengellér ZK, Khankin EV, et al. Soluble fms-like tyro- 194. Odibo AO, Goetzinger KR, Odibo L, Cahill AG, Macones GA, Nelson
sine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin DM, Dietzen DJ. First-trimester prediction of preeclampsia using
Invest. 2016;126:2561–2574. doi: 10.1172/JCI83918 metabolomic biomarkers: a discovery phase study. Prenat Diagn.
174. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE.
2011;31:990–994. doi: 10.1002/pd.2822
Preeclampsia – a state of sympathetic overactivity. N Engl J Med. 195. Bahado-Singh RO, Syngelaki A, Akolekar R, Mandal R, Bjondahl TC,
1996;335:1480–1485. doi: 10.1056/NEJM199611143352002 Han B, Dong E, Bauer S, Alpay-Savasan Z, Graham S, Turkoglu O,
175. Reyes LM, Usselman CW, Davenport MH, Steinback CD. Sympathetic Wishart DS, Nicolaides KH. Validation of metabolomic models for pre-
nervous system regulation in human normotensive and hyperten- diction of early-onset preeclampsia. Am J Obstet Gynecol. 2015;213:530.
sive pregnancies. Hypertension. 2018;71:793–803. doi: 10.1161/ e1–530.e10. doi: 10.1016/j.ajog.2015.06.044
HYPERTENSIONAHA.117.10766 196. Kelly RS, Croteau-Chonka DC, Dahlin A, et al. Integration of metabo-
176. Molino P, Veglio F, Genova GC, Melchio R, Benedetto C, Chiarolini L, lomic and transcriptomic networks in pregnant women reveals biolog-
Rabbia F, Grosso T, Mulatero P, Chiandussi L. Baroreflex control of heart ical pathways and predictive signatures associated with preeclampsia.
rate is impaired in pre-eclampsia. J Hum Hypertens. 1999;13:179–183. Metabolomics. 2017;13:7.
177. Cleary KL, Siddiq Z, Ananth CV, Wright JD, Too G, DʼAlton ME, 197. Bahado-Singh R, Poon LC, Yilmaz A, Syngelaki A, Turkoglu O, Kumar
Friedman AM. Use of antihypertensive medications during de- P, Kirma J, Allos M, Accurti V, Li J, Zhao P, Graham SF, Cool DR,
livery hospitalizations complicated by preeclampsia. Obstet Gynecol. Nicolaides K. Integrated proteomic and metabolomic prediction of term
2018;131:441–450. doi: 10.1097/AOG.0000000000002479 preeclampsia. Sci Rep. 2017;7:16189. doi: 10.1038/s41598-017-15882-9
178. Hines T, Beauchamp D, Rice C. Baroreflex control of sympa-
198. O’Gorman N, Wright D, Poon LC, et al. Multicenter screening for pre-
thetic nerve activity in hypertensive pregnant rats with reduced eclampsia by maternal factors and biomarkers at 11-13 weeks’ gesta-
uterine perfusion. Hypertens Pregnancy. 2007;26:303–314. doi: tion: comparison with NICE guidelines and ACOG recommendations.
10.1080/10641950701415598 Ultrasound Obstet Gynecol. 2017;49:756–760. doi: 10.1002/uog.17455
179. Spradley FT, Ge Y, Haynes BP, Granger JP, Anderson CD. Adrenergic 199. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnan-
receptor blockade attenuates placental ischemia-induced hypertension. cies at high risk for preterm preeclampsia. N Engl J Med. 2017;377:613–
Downloaded from http://ahajournals.org by on April 15, 2019

Physiol Rep. 2018;6:e13814. doi: 10.14814/phy2.13814 622. doi: 10.1056/NEJMoa1704559


180. Aubuchon M, Schulz LC, Schust DJ. Preeclampsia: animal models
200. Agrawal S, Cerdeira AS, Redman C, Vatish M. Meta-analysis and

for a human cure. Proc Natl Acad Sci USA. 2011;108:1197–1198. doi: systematic review to assess the role of soluble FMS-like tyrosine
10.1073/pnas.1018164108 kinase-1 and placenta growth factor ratio in prediction of pree-
181. Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endothe- clampsia: the SaPPPhirE Study. Hypertension. 2018;71:306–316. doi:
lium-dependent vascular relaxation during reduction of uterine perfusion 10.1161/HYPERTENSIONAHA.117.10182
pressure in pregnant rat. Hypertension. 2000;35:367–372. 201. Chaiworapongsa T, Romero R, Korzeniewski SJ, Cortez JM, Pappas A,
182. LaMarca B, Amaral LM, Harmon AC, Cornelius DC, Faulkner JL,
Tarca AL, Chaemsaithong P, Dong Z, Yeo L, Hassan SS. Plasma concen-
Cunningham MW Jr. Placental ischemia and resultant phenotype in trations of angiogenic/anti-angiogenic factors have prognostic value in
animal models of preeclampsia. Curr Hypertens Rep. 2016;18:38. doi: women presenting with suspected preeclampsia to the obstetrical triage
10.1007/s11906-016-0633-x area: a prospective study. J Matern Fetal Neonatal Med. 2014;27:132–
183. Davisson RL, Hoffmann DS, Butz GM, Aldape G, Schlager G, Merrill 144. doi: 10.3109/14767058.2013.806905
DC, Sethi S, Weiss RM, Bates JN. Discovery of a spontaneous genetic 202. Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ, Yeo L, Romero
mouse model of preeclampsia. Hypertension. 2002;39:337–342. R. Pre-eclampsia part 2: prediction, prevention and management. Nat
184. Bulla R, Agostinis C, Bossi F, Rizzi L, Debeus A, Tripodo C, Radillo O, Rev Nephrol. 2014;10:531–540. doi: 10.1038/nrneph.2014.103
De Seta F, Ghebrehiwet B, Tedesco F. Decidual endothelial cells express 203. Rana S, Salahuddin S, Mueller A, Berg AH, Thadhani RI, Karumanchi
surface-bound C1q as a molecular bridge between endovascular tropho- SA. Angiogenic biomarkers in triage and risk for preeclampsia
blast and decidual endothelium. Mol Immunol. 2008;45:2629–2640. doi: with severe features. Pregnancy Hypertens. 2018;13:100–106. doi:
10.1016/j.molimm.2007.12.025 10.1016/j.preghy.2018.05.008
185. Sandgren JA, Deng G, Linggonegoro DW, et al. Arginine vasopressin 204. Chappell LC, Duckworth S, Seed PT, Griffin M, Myers J, Mackillop L,
infusion is sufficient to model clinical features of preeclampsia in mice. Simpson N, Waugh J, Anumba D, Kenny LC, Redman CW, Shennan
JCI Insight. 2018;3. AH. Diagnostic accuracy of placental growth factor in women with
186. Takimoto E, Ishida J, Sugiyama F, Horiguchi H, Murakami K, Fukamizu suspected preeclampsia: a prospective multicenter study. Circulation.
A. Hypertension induced in pregnant mice by placental renin and ma- 2013;128:2121–2131. doi: 10.1161/CIRCULATIONAHA.113.003215
ternal angiotensinogen. Science. 1996;274:995–998. 205. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M,
187. Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell-triggered vas- Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl
cular transformation: maternal care before birth? Cell Mol Immunol. M, Hund M, Verlohren S. Predictive value of the sFlt-1:PlGF ratio in
2011;8:1–11. doi: 10.1038/cmi.2010.38 women with suspected preeclampsia. N Engl J Med. 2016;374:13–22.
188. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia doi: 10.1056/NEJMoa1414838
and the other hypertensive disorders of pregnancy. Best Pract Res Clin 206. Zeisler H, Llurba E, Chantraine FJ, Vatish M, Staff AC, Sennstrom M,
Obstet Gynaecol. 2011;25:391–403. doi: 10.1016/j.bpobgyn.2011.01.006 Olovsson M, Brennecke SP, Stepan H, Allegranza D, Schoedl M, Grill S,
189. Stepan H, Kuse-Föhl S, Klockenbusch W, Rath W, Schauf B, Walther Hund M, Verlohren S. The sFlt-1/PlGF Ratio: ruling out pre-eclampsia
T, Schlembach D. Diagnosis and treatment of hypertensive pregnancy for up to 4 weeks and the value of retesting [published online July 16,
disorders. guideline of DGGG (S1-Level, AWMF registry no. 015/018, 2018]. Ultrasound Obstet Gynecol. doi: 10.1002/uog.19178
December 2013). Geburtshilfe Frauenheilkd. 2015;75:900–914. doi: 207. Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine
10.1055/s-0035-1557924 F, Klein E, Lapaire O, Llurba E, Ramoni A, Vatish M, Wertaschnigg D,
190. Kaitu’u-Lino TJ, Brownfoot FC, Beard S, Cannon P, Hastie R, Nguyen Galindo A. Implementation of the sFlt-1/PlGF ratio for prediction and
TV, Binder NK, Tong S, Hannan NJ. Combining metformin and diagnosis of pre-eclampsia in singleton pregnancy: implications for
Rana et al   Preeclampsia and Vascular Disease   1111

clinical practice. Ultrasound Obstet Gynecol. 2015;45:241–246. doi: antiphospholipid syndrome refractory to antithrombotic therapy. J Clin
10.1002/uog.14799 Invest. 2016;126:2933–2940. doi: 10.1172/JCI86957
208. Manriquez Rocha B, Mbofana F, Loquiha O, Mudenyanga C,
227. Chaiworapongsa T, Romero R, Korzeniewski SJ, Chaemsaithong P,

Ukah UV, Magee LA, von Dadelszen P. Early diagnosis of pree- Hernandez-Andrade E, Segars JH, DeCherney AH, McCoy MC, Kim
clampsia using placental growth factor: an operational pilot study in CJ, Yeo L, Hassan SS. Pravastatin for the prevention of adverse preg-
Maputo, Mozambique. Pregnancy Hypertens. 2018;11:26–31. doi: nancy outcome: preeclampsia and more? J Matern Fetal Neonatal Med.
10.1016/j.preghy.2017.12.005 2017;30:3. doi: 10.3109/14767058.2015.1129779
209. Bellomo G, Venanzi S, Saronio P, Verdura C, Narducci PL.
228. Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ,
Prognostic significance of serum uric acid in women with gesta- Senadheera S, Illanes SE, Kaitu’u-Lino TJ, Tong S. Metformin as a
tional hypertension. Hypertension. 2011;58:704–708. doi: 10.1161/ prevention and treatment for preeclampsia: effects on soluble fms-
HYPERTENSIONAHA.111.177212 like tyrosine kinase 1 and soluble endoglin secretion and endothelial
210. Vyakaranam S, Bhongir AV, Patlolla D, Chintapally R. Study of
dysfunction. Am J Obstet Gynecol. 2016;214:356.e1–356.e15. doi:
serum uric acid and creatinine in hypertensive disorders of preg- 10.1016/j.ajog.2015.12.019
nancy. Int J Med Sci Public Health. 2015;4:1424–1428. doi: 229. Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RP.
10.5455/ijmsph.2015.15042015294 Randomized trial of metformin vs insulin in the management of ges-
211. Wu Y, Xiong X, Fraser WD, Luo ZC. Association of uric acid with pro- tational diabetes. Am J Obstet Gynecol. 2013;209:34.e1–34.e7. doi:
gression to preeclampsia and development of adverse conditions in ges- 10.1016/j.ajog.2013.03.022
tational hypertensive pregnancies. Am J Hypertens. 2012;25:711–717. 230. Rana S, Rajakumar A, Geahchan C, Salahuddin S, Cerdeira AS, Burke
doi: 10.1038/ajh.2012.18 SD, George EM, Granger JP, Karumanchi SA. Ouabain inhibits placental
212. August P, Helseth G, Cook EF, Sison C. A prediction model for
sFlt1 production by repressing HSP27-dependent HIF-1α pathway.
superimposed preeclampsia in women with chronic hypertension dur- FASEB J. 2014;28:4324–4334. doi: 10.1096/fj.14-252684
ing pregnancy. Am J Obstet Gynecol. 2004;191:1666–1672. doi: 231. Klingel R, Göhlen B, Schwarting A, Himmelsbach F, Straube R.

10.1016/j.ajog.2004.03.029 Differential indication of lipoprotein apheresis during pregnancy. Ther
213. Weerasekera DS, Peiris H. The significance of serum uric acid, creatinine Apher Dial. 2003;7:359–364.
and urinary microprotein levels in predicting pre-eclampsia. J Obstet 232. Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal re-
Gynaecol. 2003;23:17–19. moval of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation.
214. Massé J, Forest JC, Moutquin JM, Marcoux S, Brideau NA, Bélanger 2011;124:940–950. doi: 10.1161/CIRCULATIONAHA.111.034793
M. A prospective study of several potential biologic markers for early 233. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of soluble
prediction of the development of preeclampsia. Am J Obstet Gynecol. Fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia.
1993;169:501–508. J Am Soc Nephrol. 2016;27:903–913. doi: 10.1681/ASN.2015020157
215. Chen Q, Lau S, Tong M, Wei J, Shen F, Zhao J, Zhao M. Serum uric 234. Makris A, Yeung KR, Lim SM, Sunderland N, Heffernan S, Thompson
acid may not be involved in the development of preeclampsia. J Hum JF, Iliopoulos J, Killingsworth MC, Yong J, Xu B, Ogle RF, Thadhani
Hypertens. 2016;30:136–140. doi: 10.1038/jhh.2015.47 R, Karumanchi SA, Hennessy A. Placental growth factor reduces
216. Lam C, Lim KH, Kang DH, Karumanchi SA. Uric acid and preeclampsia. blood pressure in a uteroplacental ischemia model of preeclampsia
Semin Nephrol. 2005;25:56–60. in nonhuman primates. Hypertension. 2016;67:1263–1272. doi:
217. Magee LA, Duley L. Oral beta-blockers for mild to moderate
10.1161/HYPERTENSIONAHA.116.07286
hypertension during pregnancy. Cochrane Database Syst Rev. 2003: 235. Spradley FT, Tan AY, Joo WS, Daniels G, Kussie P, Karumanchi SA,
Downloaded from http://ahajournals.org by on April 15, 2019

CD002863. Granger JP. Placental growth factor administration abolishes placental


218. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control ischemia-induced hypertension. Hypertension. 2016;67:740–747. doi:
of hypertension in pregnancy. N Engl J Med. 2015;372:407–417. doi: 10.1161/HYPERTENSIONAHA.115.06783
10.1056/NEJMoa1404595 236. Weissgerber TL, Rajakumar A, Myerski AC, Edmunds LR, Powers RW,
219. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom
Roberts JM, Gandley RE, Hubel CA. Vascular pool of releasable soluble
E, VanDorsten P, Landon M, Paul R, Miodovnik M, Meis P, Thurnau VEGF receptor-1 (sFLT1) in women with previous preeclampsia and
G. Low-dose aspirin to prevent preeclampsia in women at high risk. uncomplicated pregnancy. J Clin Endocrinol Metab. 2014;99:978–987.
National Institute of Child Health and Human Development Network of doi: 10.1210/jc.2013-3277
Maternal-Fetal Medicine Units. N Engl J Med. 1998;338:701–705. doi: 237. Turanov AA, Lo A, Hassler MR, et al. RNAi modulation of placental
10.1056/NEJM199803123381101 sFLT1 for the treatment of preeclampsia [published online November 19,
220. Sharp A, Cornforth C, Jackson R, Harrold J, Turner MA, Kenny LC, 2018]. Nat Biotechnol. doi: 10.1038/nbt.4297
Baker PN, Johnstone ED, Khalil A, von Dadelszen P, Papageorghiou AT, 238. Sibai BM. Etiology and management of postpartum hyperten-

Alfirevic Z, STRIDER group. Maternal sildenafil for severe fetal growth sion-preeclampsia. Am J Obstet Gynecol. 2012;206:470–475. doi:
restriction (STRIDER): a multicentre, randomised, placebo-controlled, 10.1016/j.ajog.2011.09.002
double-blind trial. Lancet Child Adolesc Health. 2018;2:93–102. doi: 239. Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud
10.1016/S2352-4642(17)30173-6 JD, Ansari A, Baughman KL. Peripartum cardiomyopathy: National
221. Pels A, Kenny LC, Alfirevic Z, Baker PN, von Dadelszen P, Gluud C, Heart, Lung, and Blood Institute and Office of Rare Diseases (National
Kariya CT, Mol BW, Papageorghiou AT, van Wassenaer-Leemhuis Institutes of Health) workshop recommendations and review. JAMA.
AG, Ganzevoort W, Groom KM; international STRIDER Consortium. 2000;283:1183–1188.
STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal 240. Patten IS, Rana S, Shahul S, et al. Cardiac angiogenic imbalance

growth restriction): an international consortium of randomised pla- leads to peripartum cardiomyopathy. Nature. 2012;485:333–338. doi:
cebo-controlled trials. BMC Pregnancy Childbirth. 2017;17:440. doi: 10.1038/nature11040
10.1186/s12884-017-1594-z 241. Uraizee I, Cheng S, Moslehi J. Reversible cardiomyopathy associated
222. Hawkes N. Trial of Viagra for fetal growth restriction is halted after baby with sunitinib and sorafenib. N Engl J Med. 2011;365:1649–1650. doi:
deaths. BMJ. 2018;362:k3247. doi: 10.1136/bmj.k3247 10.1056/NEJMc1108849
223. Girardi G. Pravastatin to treat and prevent preeclampsia. Preclinical 242. Wang CN, Chang SD, Peng HH, Lee YS, Chang YL, Cheng PJ, Chao
and clinical studies. J Reprod Immunol. 2017;124:15–20. doi: AS, Wang TH, Wang HS. Change in amniotic fluid levels of multiple
10.1016/j.jri.2017.09.009 anti-angiogenic proteins before development of preeclampsia and intrau-
224. Ramma W, Ahmed A. Therapeutic potential of statins and the induction terine growth restriction. J Clin Endocrinol Metab. 2010;95:1431–1441.
of heme oxygenase-1 in preeclampsia. J Reprod Immunol. 2014;101- doi: 10.1210/jc.2009-1954
102:153–160. doi: 10.1016/j.jri.2013.12.120 243. Hansen AR, Barnés CM, Folkman J, McElrath TF. Maternal pree-

225. Brownfoot FC, Tong S, Hannan NJ, Binder NK, Walker SP,
clampsia predicts the development of bronchopulmonary dysplasia. J
Cannon P, Hastie R, Onda K, Kaitu’u-Lino TJ. Effects of pravas- Pediatr. 2010;156:532–536. doi: 10.1016/j.jpeds.2009.10.018
tatin on human placenta, endothelium, and women with severe pre- 244. Tang JR, Karumanchi SA, Seedorf G, Markham N, Abman SH. Excess
eclampsia. Hypertension. 2015;66:687–697; discussion 445. doi: soluble vascular endothelial growth factor receptor-1 in amniotic fluid
10.1161/HYPERTENSIONAHA.115.05445 impairs lung growth in rats: linking preeclampsia with bronchopulmo-
226. Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D,
nary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302:L36–
Girardi G. Pravastatin improves pregnancy outcomes in obstetric L46. doi: 10.1152/ajplung.00294.2011
1112  Circulation Research  March 29, 2019

245. Yu XD, Branch DW, Karumanchi SA, Zhang J. Preeclampsia and ret- 254. Breetveld NM, Ghossein-Doha C, van Kuijk SM, van Dijk AP, van der
inopathy of prematurity in preterm births. Pediatrics. 2012;130:e101– Vlugt MJ, Heidema WM, van Neer J, van Empel V, Brunner-La Rocca
e107. doi: 10.1542/peds.2011-3881 HP, Scholten RR, Spaanderman ME. Prevalence of asymptomatic heart
246. Wallace B, Peisl A, Seedorf G, Nowlin T, Kim C, Bosco J, Kenniston failure in formerly pre-eclamptic women: a cohort study. Ultrasound
J, Keefe D, Abman SH. Anti-sFlt-1 therapy preserves lung alve- Obstet Gynecol. 2017;49:134–142. doi: 10.1002/uog.16014
olar and vascular growth in antenatal models of bronchopulmo- 255. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM.

nary dysplasia. Am J Respir Crit Care Med. 2018;197:776–787. doi: Preeclampsia and the risk of end-stage renal disease. N Engl J Med.
10.1164/rccm.201707-1371OC 2008;359:800–809. doi: 10.1056/NEJMoa0706790
247. Newstead J, von Dadelszen P, Magee LA. Preeclampsia and future car- 256. Vikse BE, Irgens LM, Karumanchi SA, Thadhani R, Reisæter AV,

diovascular risk. Expert Rev Cardiovasc Ther. 2007;5:283–294. doi: Skjærven R. Familial factors in the association between preeclampsia
10.1586/14779072.5.2.283 and later ESRD. Clin J Am Soc Nephrol. 2012;7:1819–1826. doi:
248. Brouwers L, van der Meiden-van Roest AJ, Savelkoul C, Vogelvang 10.2215/CJN.01820212
TE, Lely AT, Franx A, van Rijn BB. Recurrence of pre-eclampsia 257. Bushnell C, Chireau M. Preeclampsia and stroke: risks dur-

and the risk of future hypertension and cardiovascular disease: a sys- ing and after pregnancy. Stroke Res Treat. 2011;2011:858134. doi:
tematic review and meta-analysis. BJOG. 2018;125:1642–1654. doi: 10.4061/2011/858134
10.1111/1471-0528.15394 258. Basit S, Wohlfahrt J, Boyd HA. Pre-eclampsia and risk of dementia
249. Berends AL, de Groot CJ, Sijbrands EJ, Sie MP, Benneheij SH, Pal R, later in life: nationwide cohort study. BMJ. 2018;363:k4109. doi:
Heydanus R, Oostra BA, van Duijn CM, Steegers EA. Shared constitu- 10.1136/bmj.k4109
tional risks for maternal vascular-related pregnancy complications and 259. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and isch-
future cardiovascular disease. Hypertension. 2008;51:1034–1041. doi: aemic heart disease in England and Wales. Lancet. 1986;1:1077–1081.
10.1161/HYPERTENSIONAHA.107.101873 260. Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy
250. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ.
Y, Adwani S, Wilkinson AR, McCormick K, Sargent I, Redman C, Leeson
Cardiovascular sequelae of preeclampsia/eclampsia: a system- P. Cardiovascular risk factors in children and young adults born to pree-
atic review and meta-analyses. Am Heart J. 2008;156:918–930. doi: clamptic pregnancies: a systematic review. Pediatrics. 2012;129:e1552–
10.1016/j.ahj.2008.06.042 e1561. doi: 10.1542/peds.2011-3093
251. Shahul S, Ramadan H, Nizamuddin J, Mueller A, Patel V, Dreixler J, 261. Jayet PY, Rimoldi SF, Stuber T, Salmòn CS, Hutter D, Rexhaj E,

Tung A, Lang RM, Weinert L, Nasim R, Chinthala S, Rana S. Activin Thalmann S, Schwab M, Turini P, Sartori-Cucchia C, Nicod P, Villena M,
A and late postpartum cardiac dysfunction among women with hyper- Allemann Y, Scherrer U, Sartori C. Pulmonary and systemic vascular dys-
tensive disorders of pregnancy. Hypertension. 2018;72:188–193. doi: function in young offspring of mothers with preeclampsia. Circulation.
10.1161/HYPERTENSIONAHA.118.10888 2010;122:488–494. doi: 10.1161/CIRCULATIONAHA.110.941203
252. Shahul S, Ramadan H, Mueller A, Nizamuddin J, Nasim R, Lopes 262. Hoodbhoy Z, Hasan BS, Mohammed N, Chowdhury D. Impact of pre-
Perdigao J, Chinthala S, Tung A, Rana S. Abnormal mid-trimester eclampsia on the cardiovascular health of the offspring: a cohort study pro-
cardiac strain in women with chronic hypertension predates super- tocol. BMJ Open. 2018;8:e024331. doi: 10.1136/bmjopen-2018-024331
imposed preeclampsia. Pregnancy Hypertens. 2017;10:251–255. doi: 263. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R.

10.1016/j.preghy.2017.10.009 Cardiovascular disease risk in women with pre-eclampsia: system-
253. Shahul S, Rhee J, Hacker MR, Gulati G, Mitchell JD, Hess P, Mahmood atic review and meta-analysis. Eur J Epidemiol. 2013;28:1–19. doi:
F, Arany Z, Rana S, Talmor D. Subclinical left ventricular dysfunction 10.1007/s10654-013-9762-6
Downloaded from http://ahajournals.org by on April 15, 2019

in preeclamptic women with preserved left ventricular ejection frac- 264. Rolnik DL, Wright D, Poon LCY, et al. ASPRE trial: performance of
tion: a 2D speckle-tracking imaging study. Circ Cardiovasc Imaging. screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol.
2012;5:734–739. doi: 10.1161/CIRCIMAGING.112.973818 2017;50:492–495. doi: 10.1002/uog.18816