Placenta 35, Supplement A, Trophoblast Research, Vol.

28 (2014) S32eS38

Contents lists available at ScienceDirect

Placenta
journal homepage: www.elsevier.com/locate/placenta

Review: Maternal and placental antioxidant response to

preeclampsia e Impact on vasoactive eicosanoids
J.-F. Bilodeau a, b, *
a
Reproductive, Maternal and Child Health, CHU de Quebec Research Center (CHUL), Québec, Canada
b
Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, Laval University, Quebec, Canada

a r t i c l e i n f o a b s t r a c t

Article history: The abnormally developed placenta is believed to be the pathophysiological cause of preeclampsia (PE).
Accepted 22 November 2013 The resulting malperfusion of the placenta in PE can be associated with fluctuations in oxygen levels,
leading to oxidative stress. How then do the placenta and the circulatory system of the mother adapt and
Keywords: respond to the increased oxidative challenge associated with PE? Many antioxidant systems have been
Vitamins shown to be upregulated or downregulated in the placenta and/or the maternal circulation during PE.
Glutathione
Such altered antioxidant response can lead to increased lipid peroxidation. Oxidation of arachidonoyl
Glutathione peroxidase
residues in phospholipids generates bioactive lipids such as F2-isoprostanes, which are known vaso-
Catalase
Superoxide dismutase
constrictors. The consequences of changes in antioxidant status can also affect signal transduction and
Coenzyme Q10 enzymatic pathways related to eicosanoid synthesis.
Eicosanoids Ó 2013 Published by IFPA and Elsevier Ltd.
Isoprostanes
Prostacyclin
Thromboxane

1. Introduction vasoactive eicosanoid pathways, using arachidonic acid (AA) as the

In a typical uncomplicated pregnancy, the increased oxygen
consumption and energy requirements for placental and fetal
growth are associated with mild oxidative stress as measured in
maternal plasma and urine [1]. Moreover, in pregnancies compli-
cated by preeclampsia (PE), the oxidative stress observed is higher
than in normotensive pregnancies [2]. PE is defined as the
appearance of hypertension and proteinuria after 20 weeks of
gestation, with an incidence of 3e7% of all pregnancies in indus-
trialized countries. The placenta is believed to be the source for the
etiology of PE, according to the classical two-stage model first
described by Redman and Roberts [3]. Although there are probably
numerous etiological causes for PE at the molecular level, all of
these lead to oxidative stress later in gestation.
This review will first discuss the placental antioxidant response
to PE-associated oxidative stress since the fetoematernal interface
is at the origin of this pathology. It will next deal with the maternal
response involved in the second stage of PE. Lastly, it will focus on
the consequences of these antioxidant changes on the various
* CHU de Quebec Research Center (CHUL), Reproductive, Maternal and Child
Health, 2705, Boulevard Laurier, Room T1-49, Quebec (PQ), Canada G1V 4G2.
Tel.: þ1 418 525 4444x46153; fax: þ1 418 654 2765.
E-mail address: jean-francois.bilodeau@crchul.ulaval.ca.
initial substrate. Two pathways will be specifically reviewed: the
cyclooxygenase (COX) and the F2-isoprostane pathways.
The COX pathway leads to the formation of biosynthesized
prostaglandins (PG), namely F2a and thromboxane A2 (TXA2), which
are known vasoconstrictors, and prostacyclin (PGI2) and PGE2,
known vasodilators [4]. The second pathway involves the non-
enzymatic oxidation of AA into numerous F2-isoprostanes [5], the
most studied representative being the classical 8-iso-PGF2a (or
iPF2a-III), an accurate marker of oxidative stress [6]. When liberated
from phospholipids at the sn-2 position by phospholipases A2, 8-
iso-PGF2a also acts as a vasoconstrictor.
2. Evidence of placental oxidative stress in preeclampsia
PE is associated with abnormal trophoblast differentiation and
invasion, resulting in an altered vascular remodeling of spiral ar-
teries [7]. This in turn leads to reduced placental perfusion and
ischemia, a source of oxidative stress [3]. Many believe that
increased placental oxidative stress in PE starts as early as at the
initiation of intervillous blood flow after w8e10 weeks of gesta-
tion. At this stage, placental pO2 rises steeply between the 10th and
12th week of gestation, with endogenous antioxidant activities like
glutathione peroxidase (GPx), superoxide dismutase (SOD) and
catalase rising accordingly in healthy pregnant women [8]. Despite

0143-4004/$ e see front matter Ó 2013 Published by IFPA and Elsevier Ltd.
http://dx.doi.org/10.1016/j.placenta.2013.11.013
 J.-F. Bilodeau / Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S32eS38 S33

this, all studies have assessed placental oxidative stress only at activities of GPx, glutathione-S-transferase (GST), Trx reductase and
delivery, due to obvious experimental obstacles. Not surprisingly, SOD were shown to be decreased in PE placentas relatively to
severe cases of PE presenting high levels of oxidative stress are controls [11,13,19e21].
often delivered much earlier than normotensive controls. Since More recently, the deficiencies or compensatory increases in
pregnancy interruptions during the last trimester are rare, can a endogenous antioxidant enzymes were pinpointed to specific iso-
preterm pregnancy or a normal term pregnancy be used as a con- forms of the various enzyme families (Table 2). Some studies have
trol for such severe cases of PE? The question remains partially also controlled for the effect of labor, an important source of bias in
unanswered, but careful statistical analysis and additional sam- protein and gene expression [9,22]. It has also been reported that
pling at different gestational ages can indicate if a given marker is GST of class pi was specifically decreased in the placenta and
stable throughout the third trimester [9]. decidua of PE women [23]. It was shown that peroxiredoxin-2 and
In addition to enhanced superoxide anion production by -3 were lower in the proteome of PE than in controls [24], whereas
placental tissue [10] and isolated trophoblast cells in vitro [11], mitochondrial peroxiredoxin-3 mRNA and protein can be rather
third-trimester placental homogenates from PE show 39% higher increased in PE pregnancies [25]. In addition, peroxiredoxin-6
hydrogen peroxide production than normotensive controls [12]. protein level was decreased in isolated cytotrophoblasts in PE
Increased levels (1.5e3-fold) of malondialdehyde (MDA), an index compared to controls [26].
of lipid peroxidation, were also observed in PE placental biopsies We demonstrated that the reported decrease of SOD activity in
[13]. Elevated levels of both free and total 8-iso-PGF2a were PE placentas may be attributed to SOD1 in the absence of labor [27],
measured in placentas from women with PE [14]. However, Staff and this result was also confirmed by a proteomic approach [24].
et al. have found a significant increase in free, but not total, 8-iso- We also showed that combination of labor and PE upregulated
PGF2a in decidua basalis and placenta in PE as compared to controls SOD1 in fetal membranes, as well as SOD2 and SOD3 in whole
[15]. placentas [27]. Moreover, we observed that GPX4 mRNA expression
Although sources of the observed oxidative stress are numerous, was deficient in PE placentas in the presence or absence of labor
they might derive in part from mitochondria, which consume most [22]. Likewise, Mistry et al. showed a reduction in GPx-1, GPx-3 and
of cellular oxygen. The leakage of ROS such as superoxide anion and GPx-4 protein content in PE placental villi, using immunohisto-
hydrogen peroxide from the respiratory chain occurs especially chemistry [28].
upon hypoxia/reoxygenation [16]. Placental mitochondria isolated Following the above overview of the placental antioxidant
from preeclampsia have been shown to be more abundant and response, which placental antioxidant deficiencies are the most
more susceptible to oxidation than normotensive controls, using pathophysiologically important in the etiology of PE? My preferred
the MDA index [17]. Other sources of oxidative stress include hypothesis is that SOD-1 and GPX-1/-3/-4 deficiencies are the key
xanthine oxidase, which generates superoxide anion. Staining of antioxidants in the progression of PE pathogenesis. Indeed, a
the latter enzyme is also higher in certain trophoblasts from PE decrease in SOD-1 level will cause an increase in superoxide anion,
placentas than in controls [18]. which then reacts with nitric oxide (NO) to form peroxynitrite. This
will in turn reduce the bioavailability of NO, a vasodilator. Moreover
3. Placental antioxidant response to preeclampsia chronic treatment with Tempol, a SOD mimetic, in the BPH/5 PE
mouse model during gestation improved fetal growth and lowered
Placental antioxidant imbalances have been strongly associated maternal blood pressure at the end of gestation, compared to C57
with the pathogenesis of PE. The main placental antioxidants and control mice [29]. Interestingly, this model of spontaneous PE dis-
enzyme activities affected in this condition are shown in Table 1. played impaired placentation and SOD-1 deficiency before the
Most studies show a decrease in non-enzymatic antioxidants such onset of higher blood pressure and proteinuria, which suggests an
as vitamin E, vitamin C, glutathione (GSH) and thioredoxin (Trx) important role of SOD-1 in the early stages of PE pathogenesis [29].
levels in PE [13,19e21]. In addition, the antioxidant enzymatic GPx deficiency is likely the second key player in the etiology of
PE, since decreases in this activity can be associated with the syn-
thesis of vasoconstrictive eicosanoids such as F2-isoprostanes and
Table 1 thromboxanes, which are known to be upregulated in PE placentas
Placental antioxidants and enzyme activities affected in PE compared to normo- [30]. Moreover, since GPx are selenoproteins, their synthesis/ac-
tensive controls.a
tivity is bound to selenium bioavailability. Indeed, Se deficiency in
/ Unchanged [ Increased Y Decreased rat can be used as a model for PE [31]. Of note, Se deficiency in rat
[Ref.] [Ref.] [Ref.] had no impact on liver and placental SOD activity. However, levels
Antioxidants of Trx reductases, which also are antioxidant selenoproteins, are
Vitamin C [19] decreased, and should not be ruled out as potential players in PE
(ascorbate)
pathophysiology. Trx reductases are linked to antioxidant enzyme
Vitamin E [20]
(a-tocopherol) peroxiredoxins since Trx acts as a reducing cofactor. However,
Coenzyme Q10 (Reviewed peroxiredoxin-3 knockout mice show placental oxidative stress
in Ref. [45]) without PE-like symptoms [32]. Thus, for the time being, peroxir-
Total GSH [65] [13,19] edoxins might therefore be excluded as major players in PE
Trx [66] [21]
Antioxidant enzyme activities
pathogenesis.
Catalase [20]
GPx [65] [19e21] 4. Evidence of maternal oxidative stress
GST [65] [19]
SOD [13,19e21] [11],b
Throughout an uneventful pregnancy, the level of 8-iso-PGF2a
Trx reductase [21]
increases significantly between the 26th and the 30th week from
GPx ¼ glutathione peroxidase; GSH ¼ glutathione; SOD ¼ superoxide dismutase; the 6- to 8-week baseline in urine, whereas this stage is reached
Trx ¼ thioredoxin.
a
Whole placenta homogenates.
later in plasma, namely at 37e41 weeks of gestation, i.e. just before
b
Trophoblast cells for this specific reference. delivery [1]. Only a few studies have looked prospectively at the
potential link between PE and oxidative stress markers. One report
S34 J.-F. Bilodeau / Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S32eS38

Table 2
Placental endogenous enzymatic antioxidants affected in PE as compared to normotensive controls: specific gene or protein expression.

Family of endogenous Reactions Symbol (gene) Specific name PE vs controls [Ref.]

antioxidants

Catalase 2 H2O2 / 2 H2O þ O2 CAT / mRNA [20]

Glutathione peroxidases
(GPxs)
Glutathione-S-transferases
(GSTs)
Peroxiredoxins (Prxs)
Superoxide dismutases
(SODs)
[ Protein [67]
H2O2 þ 2 GSH / 2 H2O þ GSSG GPX1 Classical or cytosolic (cGPx or GPx) / or Y mRNA [20,22]
Y Protein [28]
ROOH þ 2 GSH / H2O þ GSSG þ ROH GPX2 Gastrointestinal (GPx-GI) /mRNA [22]
GPX3 Extracellular or plasmatic / mRNA [22]
(GPx-P or eGPx) Y Protein [28]
GPX4 Phospholipid hydroperoxide Y mRNA [22]
glutathione peroxidase (PHGPx) Y Protein Ref. [28]
ROOH þ 2 GSH / H2O þ GSSG þ ROH GST Class pi Y Protein (placenta þ
decidua) [23]
Prx[-SH]2 þ H2O2 / Prx[-S-]2 þ 2H2O PRDX1 e e
Prx[-SH]2 þ ROOH / Prx[-S-]2 þ H2O þ ROH PRDX2 e Y Protein Ref. [24]
PRDX3 Thioredoxin-dependent peroxide [ mRNA [36] þ Y[
reductase, mitochondrial protein Ref. [24,25]
PRDX4
Prx[-S-] þ Trx[-SH]2 / Prx[-SH]2 þ Trx[-S-]2 PRDX5 e e
PRDX6 e Y Protein (isolated
cytotrophoblasts) [26]
2O: þ
2 þ 2 H / O2 þ H2O2 SOD1 Cu,Zn SOD, cytosolic Y mRNA, [20,27]
SOD2 Mitochondrial (MnSOD) / mRNA þ protein Ref. [27]
SOD3 Extracellular SOD (EC-SOD) / mRNA þ protein Ref. [27]

GSH ¼ glutathione (reduced form); GSSG ¼ Glutathione disulfide (oxidized form); ROOH ¼ Lipid hydroperoxide; Trx ¼ Thioredoxin. Y ¼ downregulated; [ ¼ upregulated;
/ ¼ unchanged.

showed an increase of 8-iso-PGF2a as early as at 15 weeks of
gestation in women who would later develop PE (5-fold higher risk)
compared to controls [33]. Accordingly, 8-iso-PGF2a level was 1.7-
fold higher in the amniotic fluid of PE than normotensive preg-
nancies [34]. The source of F2-isoprostanes early in pregnancy is
still uncertain, and might originate from both the placenta and the
mother.
Many studies showed an increase of MDA and/or F2-isoprostane
in PE when the syndrome occurs [2,14,35e37]. At the third
trimester, there is a link between the severity of PE and the level of
MDA in plasma [36,37]. However, there have been conflicting re-
ports for 8-iso-PGF2a levels in PE in both plasma and urine [38]. This
could arise from the ratio of free to bound F2-isoprostanes, which
has not been systematically assessed. Free and total levels of 8-iso-
PGF2a were measured in fluids such as saliva, urine and plasma in
normotensive and PE pregnancies; Mckinney et al. reported higher
levels of free, but not total 8-iso-PGF2a in the plasma of PE patients
compared to normotensive pregnancies [2]. Since only free 8-iso-
PGF2a possesses vasoactive properties, this increase partly explains
the higher blood pressure found in PE. Indeed, the highest levels of
free 8-iso-PGF2a were found in severe cases of PE (160 mm Hg
systolic, 110 mm Hg diastolic, proteinuria >300 mg/24 h).
Another explanation for the conflicting levels of oxidative stress
markers found in PE could be that F2-isoprostane production
competes with that of isofurans and/or F3-isoprostanes as well as
that of F4-isoprostanes (neuroprostanes) derived from the oxida-
tion of eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA), respectively (Fig. 1 for typical chemical structure). Indeed, in
a recent study, levels of isofurans and neuroprostanes, but not F2-
isoprostanes, were significantly higher in the blood of third
trimester PE patients compared to controls [39].
5. Overview of maternal antioxidant response to
preeclampsia
Since most maternal tissues are difficult to obtain during preg-
nancy, levels of antioxidants in PE patients have generally been
measured in the blood stream. Women affected by PE have clearly
altered blood levels of antioxidants. Here we separately review
exogenous antioxidants such as vitamins and the enzymatic
endogenous antioxidant response in the maternal circulation.
5.1. Maternal antioxidant vitamins and other exogenous
antioxidants
Plasma ascorbate reserves gradually decrease throughout an
uneventful pregnancy. This reserve of a soluble antioxidant is
further lowered by 20e50% in PE pregnancies [37,40e42] in some,
but not all studies [19,43]; the top half of Table 3 summarizes these
studies. Concentrations of vitamin E, a lipophilic antioxidant, were
found unchanged [41,44], increased [9,37,43] or decreased in the
maternal circulation in PE pregnancies [42]. Also, total CoQ10, a
vitamin-like antioxidant, was shown to be unchanged or decreased
in the maternal circulation in PE compared to controls (reviewed in
Ref. [45]).
Of note, our group reported no increase of the total CoQ10 level
in plasma, but rather an increase in the ratio of oxidized to reduced
forms of CoQ10 in the blood of PE mothers [9]. Our study also
indicated that CoQ10 is a more sensitive marker of oxidative stress
than vitamin E in PE. Furthermore, we showed that ubiquinol-10
(oxidized CoQ10) was correlated with a-tocopherol (the main
vitamin E form accumulating in humans) levels exclusively in PE
pregnancies [9]. The positive correlation between ubiquinol-10 and
a-tocopherol might thus represent a coordinated defense mecha-
nism against oxidative stress during PE.
The aforementioned studies suggest that exogenous antioxi-
dants could be used for the prevention of PE to compensate for
antioxidant deficiencies. So far, treatments with a-tocopherol and
vitamin C were unsuccessful overall in preventing PE. However,
selenium supplementation to increase GPx, coenzyme Q10 and
carotenoid levels looks promising, although more studies are still
needed to confirm this effect (reviewed in Ref. [45]).
5.2. Maternal endogenous antioxidant response
The bottom half of Table 3 shows a summary of the studies that
investigated the maternal endogenous antioxidant response to PE.
In comparison to normotensive pregnancies, the plasma or
 J.-F. Bilodeau / Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S32eS38 S35

Fig. 1. Eicosanoids in the pathophysiology of preeclampsia: a hypothesis from the current state of knowledge. The balance of vasoactive eicosanoids shifts toward vasoconstriction
in preeclampsia because of a deficient level of antioxidants. AA: arachidonic acid; COX: cyclooxygenase; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; GPx-4: gluta-
thione peroxidase-4 or phospholipid hydroperoxide glutathione peroxidase (PHGPx); IPR: prostacyclin receptor; isoPs, isoprostanes; SOD-1: superoxide dismutase-1 or Cu,Zn SOD;
TPR: thromboxane receptor.

erythrocyte concentrations in NO and lipid peroxides were
elevated, with a concomitant decrease in catalase and SOD activ-
ities in red blood cells from PE cases [44,46]. Also, another team
found that the serum levels of lipid peroxides were significantly
increased, while SOD activity and GSH level in erythrocytes were
significantly decreased in PE women compared to controls [47]. In
addition, mitochondrial SOD activity was also reduced in compar-
ison to third trimester controls in red blood cells [46].
Lipid peroxidation and total GPx activity have been shown to
increase in plasma and erythrocytes of patients with PE and HELLP
(hemolysis, elevated liver enzymes, and low platelet count) syn-
drome, while GST, glutathione reductase and SOD activities
remained unchanged [48]. Funai et al. reported no difference in
plasma GPx activity in the second and third trimester between
controls and PE [49], while Mistry et al. reported decreased plasma
GPx in PE [50]. Interestingly, we have shown that higher GPx-1 and
GPx-4 mRNA and protein expression occurs in blood lymphocytes
and monocytes from PE than normotensive control subjects [51].
Overall, there is no consensus on the status of endogenous anti-
oxidant systems in PE, although all studies have shown at least one
alteration of these systems in plasma, leukocytes or erythrocytes.
6. Impact of oxidative stress on eicosanoids in PE
6.1. Effects of PE on the COX pathway
Disrupted vasoactive eicosanoid synthesis appears to be a key
component in PE physiopathology. Two key metabolites of the COX
pathway derived from arachidonic acid were shown to be affected,
namely prostacyclin, and TXA2. Prostacyclin synthase is inhibited
by peroxides whereas thromboxane synthase can even be stimu-
lated [52]. Indeed, t-butyl-hydroperoxide, a classical substrate for
seleno-GPx, was shown to stimulate the release of TXB2, a stable
TXA2 metabolite, in isolated human placental cotyledon [53]. Also,
TXA2 synthase was shown to be higher or unchanged in PE pla-
centas compared to controls, as demonstrated by in situ hybridi-
zation and immunohistochemistry [54,55]. In contrast, 6-keto-
PGF1a, a stable metabolite of PGI2, was shown to be decreased,
unchanged or even increased in PE [9,30]. Similar findings have
been obtained from in vitro studies. Villous core tissues isolated
from PE pregnancies produced more thromboxane than controls
[56]. Isolated trophoblast cells cultured in vitro from PE produce
more thromboxane than control trophoblast cells in the first days of
S36 J.-F. Bilodeau / Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S32eS38

Table 3 which might correlate better with PE, as mentioned earlier [39].
Maternal antioxidants and enzyme activities affected in PE compared to normo- Important information could be drawn from the simultaneous
tensive controls.
analysis of several isomers of F2/3/4-isoprostanes as they may be
/ Unchanged [ Increased Y Decreased formed and eliminated differentially, according to the physiological
[Ref.] [Ref.] [Ref.] state or disorder [60]. Of note, isofuran isomers are produced in
Antioxidants competition with F2-isoprostanes at a significant higher rate than
Vitamin C Plasma [19,43] Plasma 8-iso-PGF2 in conditions of enhanced oxygen tension, and should
(ascorbate) [37,40e42]
not be overlooked as a marker in the future [61].
Vitamin E Plasma [41] Plasma Plasma [42]
(atocopherol) RBC [44] [9,37,43] The F2-isoprostanes are released from phospholipids by phos-
Coenzyme Q10 Plasma (reviewed Plasma, serum pholipases A2 and act as vasoconstrictors. Free 8-iso-PGF2a acti-
in Ref. [45]) (reviewed in vates the same receptor as TXA2, namely the thromboxane receptor.
Ref. [45])
However, there is also indirect evidence for isoprostane receptors
Total GSH Blood [43] Plasma [13]
RBC [43,44] RBC [47]
(reviewed in Ref. [62]). Interestingly, 8-iso-PGF2a is more abundant
Total thiols Plasma [41] Plasma [19] in plasma than TXA2, along with a longer expected half-life in vivo
Antioxidant enzyme activities [62]. The F2-isoprostanes are probably underestimated regulators
Catalase RBC of the vascular tone in comparison with the thromboxane to
[35,43,44,46]
prostacyclin ratio in the placenta. F2-isoprostanes might have
GPx Plasma [19,48] RBC [48] Blood [40]
RBC [43,44] Plasma [36] potentially three effects on the placenta: 1) limiting trophoblast
RBC [35] invasion, as demonstrated in vitro using a choriocarcinoma cell line
GR RBC [48] RBC [44] [5]; 2) increasing vasoconstriction within the placenta, as shown
GST RBC [48] RBC [44] with human placental small arteries [63]; and 3) promoting lipid
SOD Plasma [19,46] RBC [37] Blood [40]
RBC [37,48] Plasma
deposition in spiral arteries [64].
[13,19,36,43]
RBC
7. Conclusion
[35,44,46,47]
Mitochondrial Plasma [46] RBC [46]
SOD The exact nature of antioxidant deficiencies in PE is still debated
GPx ¼ glutathione peroxidase; GSH ¼ glutathione; GR ¼ glutathione reductase;
today. Many potential biases may occur among studies with pla-
RBC ¼ red blood cells; SOD ¼ superoxide dismutase. centas, such as the sampling procedure, the mode of delivery and
the normalization procedure for quantitative RT-PCR and protein
determination, which all might account for the observed discrep-
culture, while prostacyclin and PGE2 production remains unaf-
ancies [27]. Nonetheless, there is clearly evidence for a key role of
fected [57]. The ratio of thromboxane to prostacyclin is therefore
oxidative stress in PE, as evidenced throughout this review. Despite
important due to their antagonistic action on vascular tone, and
some contradictory results, SOD-1 and GPX-4 deficiencies in the
should be considered as a whole.
In contrast to the specific alteration of antioxidants, it has been placenta appear to occur consistently in PE. Interestingly, deficient
GPx expression might promote an increased thromboxane to
almost universally accepted since the mid-80s that the throm-
boxane to prostacyclin ratio is increased in the placenta during PE prostacyclin ratio and 8-iso-PGF2a levels (Fig. 1) [30].
Moreover, whether ROS are initiators and/or promoters of PE
pregnancies [58] and in the maternal circulation [59]. The altered
eicosanoid production was associated with decreased vitamin E remains unclear. However, as mentioned above, some indicators of
oxidative stress such as F2-isoprostanes are significantly increased
levels in severe cases [59]. However, recent evidence shows that
this may not always be the case under very specific circumstances. in plasma and amniotic fluid early in pregnancy, i.e. around 16
weeks, compared to controls [33,34]. This could indicate leakage of
For instance, the thromboxane to prostacyclin ratio is negatively
correlated with total vitamin E and the CoQ10 oxidized/reduced F2-isoprostanes from the placenta. The study of non-conventional
eicosanoids such as isoprostanes should be expanded. For
ratio in plasma [9]. Since in some cases of PE vitamin E may in fact
increase, a decreased thromboxane to prostacyclin ratio can be example, class VI F2-isoprostane regioisomers are more abundant
than the classical 8-iso-PGF2a, a class III isomer, and may better
observed instead [9].
characterize oxidative stress in PE [6]. Finally, the maternal and
placental antioxidant endogenous responses might be related
6.2. The isoprostane theory in PE revisited either to the etiological cause of PE or to the inter-individual
response to oxidative stress, which are all influenced by dietary,
Reactive oxygen species (NO, O 2 , H2O2) generated by oxidative genetic and immunological factors. Clearly, much research is still
stress have extremely short half-lives, making their direct in vitro needed in this important field.
measurement very difficult, and virtually impossible in tissues. In
contrast to other oxidative stress markers like MDA-thiobarbituric
acid (TBA) adduct, which need to be generated immediately prior Conflict of interest statement
to their measurement (peroxidability index), the F2-isoprostanes
may inform on the exact state of membrane phospholipid oxidation The author declares there is no conflict of interest.
at a given time. There are 64 possible F2-isoprostane isomers, which
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