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Compendium on the Pathophysiology and

Treatment of Hypertension
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.
© 2019 American Heart Association, Inc.
Circulation Research is available at DOI: 10.1161/CIRCRESAHA.118.313276

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
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
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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
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- 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
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at risk for pulmonary hypertension into their teenage years American College of Obstetricians and Gynecologists’ Task Force on
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2. Hogan MC, Foreman KJ, Naghavi M, Ahn SY, Wang M, Makela
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