Vascular biology of preeclampsia

Authors


Rose P. Webster, Department of Obstetrics & Gynecology, University of Cincinnati, College of Medicine, PO Box 670526, Cincinnati, OH 45267-0526, USA.
Tel.: +1 513 558 5630; fax: +1 513 558 6138.
E-mail: rose.webster@uc.edu

Abstract

Summary.  Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, resolves on delivery of the placenta. Normal pregnancy is itself characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. This is exacerbated in preeclampsia with an associated breakdown of compensatory mechanisms, eventually leading to placental and vascular dysfunction. The underlying pathology of preeclampsia is thought to be a relatively hypoxic or ischemic placenta. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can interact to produce peroxynitrite a powerful prooxidant that covalently modifies proteins by nitration of tyrosine residues, to possibly alter vascular function in preeclampsia. The linkage between placental hypoxia and maternal vascular dysfunction has been proposed to be via placental syncytiotrophoblast basement membranes shed by the placenta or via angiogenic factors which include soluble flt1 and endoglin secreted by the placenta that bind vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in the maternal circulation. There is also abundant evidence of altered reactivity of the maternal and placental vasculature and of the altered production of autocoids in preeclampsia. The occurrence of preeclampsia is increased in women with preexisting vascular disease and confers a long-term risk for development of cardiovascular disease. The vascular stress test of pregnancy thus identifies those women with a previously unrecognized at risk vascular system and promotes the development of preeclampsia. Preexisting maternal vascular dysfunction intensified by placental factors is possibly responsible for the individual pathologies of preeclampsia.

Introduction

Two potentially interrelated events: a relative placental hypoxia/ischemia linked to diffuse maternal endothelial cell activation, appear to underlie the clinical features of preeclampsia. The majority of individuals who develop preeclampsia do so at or close to term when prompt delivery of the fetus is associated with good maternal and fetal outcome [1]. However, a proportion of women develop more severe early onset disease (<34 weeks gestation) which is associated with increased fetal and maternal morbidity and mortality [2]. Whether these two phenotypes (mild late onset and severe early onset) represent two differing pathophysiologies (placental vs. maternal) is currently under debate. The increases in plasma volume, cardiac output and heart rate combined with decreasing blood pressure [3] during pregnancy, together constitute the largest cardiovascular challenge that the maternal system will ever see, equivalent to a cardiac stress test. Individuals who fail this stress test may be those who develop preeclampsia, particularly the early onset type. It is possible that preexisting altered vascular function/reactivity resulting from a systemic response to inflammation and oxidative/nitrative stress in the mother arising from an inadequately perfused placenta is the underlying cause of preeclampsia. This review will discuss the pathophysiology of preeclampsia, elaborating specifically on the vascular changes with particular emphasis on the role of oxidative nitrative stress in altering vascular reactivity and thus contributing to vascular dysfunction.

Maternal vascular remodeling in pregnancy and preeclampsia

Dramatic changes in the cardiovascular system occur throughout gestation beginning soon after conception presumably with the objective of increasing blood flow and nutrient delivery to the fetal-placental unit. Blood volume increases from 6 to 8 weeks gestation onwards by 45% to reach approx 5 litres at 32-weeks gestation [4]. The increase in red blood cell mass (20–30%) leading to physiologic hemodilution, reduces blood viscosity, thus potentially protecting from the predisposition for thromboembolic events in pregnancy [5] and permitting placental perfusion. Cardiac output (heart rate × stroke volume) increases 30–50% in pregnancy [6]. Normal pregnancy is associated with increased endothelium-mediated relaxation, blunted response to vasoconstrictors (ang II, epinephrine) and increased flow-mediated dilation [7]. Blood flow to the uterus increases tenfold in gestation (from 2% to 17% of cardiac output) reaching 500–800 mL min−1 at term, half of which goes to the placental intervillous space to sustain the developing placenta and fetus [8]. Studies in various animal models have shown that reductions in uteroplacental blood flow can lead to a hypertensive state that closely resembles preeclampsia [9].

Modification of the placental bed arteries to reach a high-flow, low-resistance state to support this increased blood flow is achieved by extravillous trophoblast-mediated remodeling of spiral arteries with replacement of endothelium by trophoblasts [10]. Placental bed biopsies from women with preeclampsia show that physiological changes in the arteries found in normal pregnancies are restricted, being limited to decidual portions of the vessels or absent altogether [11,12]. The mean external diameters of the spiral arteries in women with preeclampsia are less than half of similar vessels from uncomplicated pregnancies. The decreased diameter would result in reduced placental perfusion which has been confirmed by Doppler ultrasound [13]. Abnormal expression of endothelial receptors on invading cytotrophoblasts has been proposed to be the cause of defective invasion of both endovascular and interstitial trophoblasts found in preeclampsia [14,15]. Immunostaining of preeclamptic placental bed biopsies show very low levels of VE-cadherin, VCAM-1 and α,β integrins [16]. Vascular endothelial growth factor and Flt-1 (VEGF–Flt-1) interactions control transformation from epithelial to endothelial phenotype on the invading cytotrophoblasts [17]. Cytotrophoblast immunostaining for VEGF and Flt-1 is reduced in preeclampsia [18]. VEGF–Flt-1 interaction also induces release of NO [19], which in turn up regulates activity and expression of proinvasive MMP2 and MMP9 [20]. Defective NO synthesis causes vasoconstriction and inadequate perfusion [21]. The resultant placental hypoperfusion and intermittent perfusion creates an environment of hypoxia-reoxygenation that favors oxidative damage.

The role of the placenta in maternal vascular dysfunction

The link between abnormalities in trophoblast invasion and generalized maternal endothelial dysfunction seen in preeclampsia may be via release of placental factors [22]. Placental hypoxia resulting from inadequate trophoblast invasion accelerates the apoptotic cascade in villous trophoblast that ends with formation of syncytial knots and shedding of syncytiotrophoblast basement membrane fragments (STBM) into the maternal circulation. Several other factors, including leukocyte and platelet membrane particles, reactive oxygen species, activated neutrophils, cytokines, growth factors, angiogenic factors and hormones are also released in the process. These factors will then interact with maternal vascular endothelium which may already be damaged.

STBM, microparticles and apoptosis

Although STBM are found in the blood of normal pregnant women, their shedding is increased due to accelerated trophoblast apoptosis in preeclampsia thus activating a systemic inflammatory response [23]. STBM may also directly damage the endothelium [24], activate neutrophils and exacerbate the inflammatory response [22].The altered relaxation response of preconstricted maternal omental arteries perfused with STBM show that deported microvilli are capable of causing maternal endothelial cell damage and dysfunction [25]. Microparticles from preeclamptic women have been shown to induce vascular hyporeactivity in human omental small arteries [23] and in aortas obtained from both pregnant [26] and non-pregnant mice [23]. This may lead to endothelial dysfunction as part of the widespread intravascular inflammation [Fig. 1].

Figure 1.

 Contributors to endothelial cell injury.

Altered vascular reactivity in preeclampsia

Abnormal endothelial function exemplified by increased circulating levels of fibronectin and von Willebrand factor, markers of endothelial cell injury, is found in women with preeclampsia [27]. Decreased production of NO, prostacyclin and increased production of thromboxane, endothelin and increased vascular reactivity to Ang II in preeclamptic women also suggest abnormal endothelial function [27,28]. Altered vascular reactivity and endothelial dysfunction have been demonstrated prior to the subsequent onset of preeclampsia in several studies, including those using plasma from women with adverse Doppler flow velocity waveforms [29], decreased flow-mediated dilation of the brachial artery [30] and impairment of calf blood flow [31,32]. Several other studies have demonstrated evidence of altered vascular reactivity [33,34], or improvement of vascular reactivity on antioxidant supplementation [33] and endothelial dysfunction [33,35] in postpartum women after a preeclamptic pregnancy. Most studies, point to a damaged endothelium deficient in its hemostatic function, ultimately producing vasoconstriction.

VEGF, PLGF, Endoglin and sFlt-1

The evidence of abnormal placentation being involved in preeclampsia predicates that alterations in levels of biochemical markers of placental development would be reflected in maternal circulation. Synthesis and action of angiogenic growth factors [VEGF, soluble fms like tyrosine kinase (sflt-1), placental growth factor (PIGF) and endoglin] and their receptors in the uterine bed and placenta itself are crucial for normal placental development and pregnancy [16,36]. VEGF, secreted in response to tissue hypoxia and endothelial cell damage, has been proposed to be an useful marker of early vascular damage [37]. Therefore changes in circulating levels of these factors may identify those pregnancies predestined to develop preeclampsia. However, the current data relating to these angiogenic factors are inconsistent, explained in part by differences in methodology, experimental designs and patient heterogeneity among the studies. Most of these studies are performed after preeclampsia has been clinically diagnosed and therefore the utility of measurement of these angiogenic factors as predictors of the disease remain questionable. A recent workshop report seems to suggest that the positive predictive value of the changes in these factors is low for preeclampsia and also have been observed in patients destined to deliver small-for-gestational age (SGA) babies [38]. Recently, other proteins in the maternal serum such as activin A, inhibin A, PAPP-A and PP13 appear to be more promising as markers for preeclampsia [39]. PP13 screening in combination with Doppler has been shown to have a detection rate of 90% for preeclampsia [40].

Sflt-1, produced by alternative splicing of VEGF-R1 mRNA [41], appears to be a central regulator of angiogenesis, by its binding to potent angiogenic and mitogenic factors such as VEGF and PIGF [42]. Interaction of VEGF with its receptors (VEGFR-1 and VEGFR-2 [43] is prevented by sFlt-1 [44], which in turn results in low circulating maternal levels of free or bioactive VEGF [45]. Some studies report serum VEGF to be a promising marker in the prediction of early-onset preeclampsia [46], yet others report undetectable levels [47]. Similar observations have also been noted with PIGF, with some showing a decrease [42,48] and others no significant differences [49].

Two key antiangiogenic factors that give the highest strength of association with preeclampsia outcome are sflt-1 and soluble endoglin [42,50]. Increased sflt-1 levels (placental and peripheral blood mononuclear cells [48,51]) in preeclamptic women presents sflt-1 as a more attractive candidate marker for preeclampsia. This is reinforced by studies demonstrating its predictive value in preeclampsia [42], overexpression in rat models of preeclampsia [48,52], direct correlation with the severity of proteinuria [53] and increased incidence of preeclampsia in women bearing fetuses with trisomy on chr 13 (location of sflt-1 genes) [54]. Despite extensive data indicating a strong correlation between sflt-1 levels and presence of preeclampsia, some preeclamptic women have sflt-1 well within the normal range and vice versa [55]. Endoglin, a co-receptor for transforming growth factor (TGF) β1 and β3, has been shown to increase vascular permeability and induce modest hypertension in overexpression studies in rodents [56]. A increase in circulating levels of soluble endoglin seen 2–3 months before the onset of preeclampsia are associated with a increasing sFlt1:PlGF ratio [42].

EPC

In vitro and in vivo studies support the existence of a pool of endothelial progenitor cells (EPC) in the bone marrow, capable of angiogenesis or vascular repair in response to ischemia or vascular injury [57]. Potentially, EPC can play an important role in regulating vascular homeostasis during pregnancy and may represent a common cellular pathway linking cardiovascular risk factors and endothelial dysfunction with preeclampsia [58]. Both a decrease [59] as well as an increase in EPCs [60] with increasing gestational age in a normal pregnancy have been reported. However, these studies were carried out using different methods. Association of pregnancy with mobilization of EPCs into the circulation has been demonstrated [61]. Although reduced circulating EPC levels are observed in the presence of established cardiovascular risk factors [62], this is not apparent in preeclampsia [58]. Reports of no change [59] in EPC numbers in preeclampsia or decreased numbers of EPC-CFUs and increased senescence of EPCs in patients with pre-eclampsia compared with gestationally matched controls [63] validate this opinion. An increase in the proliferative response of preeclamptic EPCs after stimulation with TNF-alpha and angiotensin II compared with cells from normotensive pregnancy has been observed [59]. Repair of vascular injury by estrogen involving NOS-dependent mobilization of bone-marrow derived EPC [64] further supports a role for EPCs in vascular distress observed in preeclampsia.

Vasoactive agents in pregnancy and preeclampsia

Renin angiotensin system  The role of the renin angiotensin system (RAS) in pregnancy and preeclampsia has been extensively reviewed in the past. More recently, the description of agonistic antibodies to the angiotensin receptor (AT1-AA) in preeclampsia [65] and their increased concentration in a transgenic rat model of preeclampsia [66] has generated much interest in their role. Although these data are provocative, AT1-AAs have not been temporally correlated with or definitively shown to directly cause the clinical characteristics of preeclampsia [67]. A recent report [68] shows that the key features of preeclampsia can be induced in pregnant mice after injection of AT1-AAs from women with preeclampsia.

Nitric oxide  In view of the well-known physiological roles of nitric oxide as a vasodilator, in attenuating responsiveness to vasopressors and increasing uteroplacental blood flow [69], an up-regulation of the placental and maternal NO system during pregnancy and decrease with preeclampsia is empirically expected. This could occur in preeclampsia by either (i) alterations in NOS gene expression and activity, (ii) decreased substrate levels for NOS, (iii) increased inhibitors of NOS or (iv) increased degradation of NO per se. While an up-regulation of total NO synthesis is seen in normal pregnancy data from studies examining preeclamptic pregnancy are conflicting [70–72]. The placenta can produce NO from the endothelial and inducible NOS isoforms which we have shown to be expressed in syncytiotrophoblast and hofbauer cells [73–75]. Our own data show eNOS expression to be elevated in the placental vascular endothelium of preeclamptic women [76], which may well be a compensatory mechanism. An arginine (substrate) deficiency documented in preeclampsia [77] in addition to causing decreased NO can result in increased superoxide formation leading to NO degradation and peroxynitrite formation. Increased endothelial protein nitration in the presence of decreased arginine uptake in maternal aortic rings from pregnant rats clearly demonstrates this pathway [78]. Elevated levels of the natural NOS inhibitor asymmetric dimethyl arginine (ADMA) seen in preeclampsia [79–81] and increased blood pressure [82] and fetal growth restriction [83] caused by the synthetic inhibitor NG-nitro-L-arginine methyl ester L-NAME in rat models support the theory of reduced NO activity being a cause or result of the pathology observed in preeclampsia. Observations of declining ADMA [80] levels with gestational age in a normal pregnancy and association of abnormal uterine artery Doppler waveforms with high ADMA concentrations [81] support the role of endogenous NOS inhibitors adversely affecting maternal vasodilation and blood pressure. Altered ADMA concentrations are also observed in intrauterine growth restriction (IUGR) patients without preeclampsia [81]. While compelling, these data do not definitively prove an etiologic role for reduced NO in the pathophysiology of preeclampsia. Studies that determine NO metabolites as an indirect measure of NOS activity have been confusing with some showing no change [84], an increase [85] or a decrease [86], in circulating/urinary levels, and others an increase in metabolite levels in umbilical vessels [87] and amniotic fluid [88] of women with preeclampsia [71]. Nitric oxide levels in addition to controlling vasodilation can also influence the level of oxidative (superoxide formation) and nitrative (peroxynitrite) stress in the placental and maternal vasculature, which in turn can influence protein activity, function and vascular reactivity.

Oxidative stress

Oxidative stress, an increase of reactive oxygen species over scavenging by anti-oxidants, may be the point at which multiple factors converge resulting in endothelial dysfunction and the clinical manifestations of preeclampsia. The placenta in mammals is the essential interface between maternal circulation carrying O2 rich blood and the fetal circulation. Embryonic and fetal cells are particularly sensitive to oxidative stress because of their extensive cell divisions and therefore the exposure of their DNA [89]. Placental syncytiotrophoblast, being the outermost tissue of the conceptus, is particularly sensitive being exposed to the highest concentrations of O2 coming from the mother and because it contains very low antioxidant enzymes, especially early in pregnancy. Pregnancy itself is therefore a state of oxidative stress as a result of increased maternal metabolism and the metabolic activity of the placenta. The hypoxic placenta resulting from inadequate trophoblast invasion exhibits increased oxidative stress in preeclampsia as manifested by increased free radical formation, increased placental lipid peroxides [90], isoprostanes (peroxidation products of arachidonic acid) and reduced antioxidant defenses [91]. The highly vascular nature of the placenta, the fact that it is normally well oxygenated and has a large mitochondrial and macrophage content implies it is largely responsible for higher superoxide generation than most organs [92]. Maternal metabolic disorders such as diabetes, which are associated with an increased generation of oxygen-free radicals, are known to be associated with a higher incidence of miscarriages, vasculopathy and fetal structural defects, indicating that the mammalian conceptus can be irreversibly damaged by oxidative stress. Increased oxidative stress in the placenta of women with preeclampsia is well documented [91].

Four major sources of superoxide are the mitochondrial electron transport chain, NADPH-oxidase (NOX), nitric oxide synthase (NOS) and xanthine oxidoreductase (XO) [93]. In addition to our demonstration of increased levels of NOX [94], others have demonstrated a reduction in heme oxygenase [95], an indirect source of superoxide and increased activity of xanthine oxidase [96] in preeclampsia. Decreased antioxidant levels have been observed in the case of enzymatic antioxidants such as SOD (maternal and placental), glutathione peroxidase, glutathione-S-transferase [97,98] and also non-enzymatic antioxidants such as total thiols in plasma of preeclamptic women [99], vitamin E and carotenoids (vitamin A, β-carotene and lycopene) [91] in preeclampsia. Contradictory findings have also been reported for the enzymatic antioxidants studied, doubtless as a result of differences in patient groups and severity of disease. Several studies have reported that placental glutathione, glutathione peroxidase or catalase activity are increased in preeclampsia, presumably as a result of an adaptive response [99], and no change or increase in levels of vitamin E and carotenoids have also been observed [91,100,101].

Antioxidant trials underscore the importance of oxidative stress in the pathology of preeclampsia. However, two recent large antioxidant trials seem to indicate that antioxidant supplementation do not reduce the risk of preeclampsia and is associated with a higher incidence of complications [102,103]. Although treatment when the clinical syndrome is evident has so far proved to be futile, vitamin intervention early in pregnancy could assist the adaptive maternal response, thereby normalizing the effects of oxidative stress [97].

Nitrative stress

The presence of both superoxide and NO in close proximity leads to the generation of peroxynitrite (ONOO) and nitrative stress [104]. Peroxynitrite (ONOO) formation by the biradical reaction of NO and O2 is extremely fast and will occur at or near a diffusion-limited rate [104]. Many proteins have been reported to be nitrated [105]. Protein nitration is a covalent modification that can lead to either gain of function or loss of protein function [106]. We have identified some placental proteins such as p38 MAP Kinase, P2X4 [107–109] and p53 (unpublished data) to be nitrated and have discussed in detail the functional significance of nitration on placenta [110].

Protein tyrosine nitration is seen in normal physiologic conditions, but is increased in pathologic conditions including many inflammatory conditions suggesting it is a disease marker, more so for cardiovascular disease [105]. Tyrosine-nitrated proteins have been detected in several compartments of the cardiovascular system [105] signifying the role of nitration in vascular stress. We have demonstrated peroxynitrite formation in the placenta [111–113]. Nitrotyrosine, the footprint of peroxynitrite formation, has been found in higher amounts in placental [112] and maternal vasculatures [114] from preeclamptic women, that may either be a cause or consequence of the disease. Our observations of alterations in vascular reactivity and nitrotyrosine levels with peroxynitrite treatment of the normal placenta to resemble that observed in placentae from pregnancies complicated by either pre-eclampsia or pregestational diabetes [115] suggests that peroxynitrite can influence vascular reactivity. Vascular hyporeactivity and nitrotyrosine immunostaining induced by treatment of mouse aortas with microparticles from preeclamptic women in vivo [23] clearly supports a causative role in preeclampsia. More recently, peroxynitrite has been shown to be critically involved in transducing the angiogenic signal of VEGF, another effector of vascular function [116]. The observation of higher blood pressure associated with increased protein nitration in transgenic mice overexpressing Rac1 supports a clear role for peroxynitrite in regulating blood pressure [117]. The association of nitrotyrosine levels with coronary artery disease risk and the reduction of disease risk, with concomitant decrease in NT levels on statin therapy underscores the effects of nitrative stress on the vasculature [118]. In addition to the damaging effects of protein nitration brought about by peroxynitrite, clearly its greatest damage is on vascular tone caused by the degradation of NO to form peroxynitrite, in one of the fastest reactions known. Peroxynitrite can also nitrate and alter the function of crucial vascular proteins such as NOS [119], prostacyclin synthase [120] and cyclooxygenase [121], thus further disrupting vascular functions. It is attractive to speculate that protein nitration possibly provides the common effector of inflammation mediated oxidative stress resulting from either preexisting maternal cardiovascular risk factors including obesity or from a combination of maternal and placental vascular dysfunction.

Cardiovascular disease and preeclampsia

Overall a woman’s chances of developing preeclampsia may be the result of a variable interaction of placental dysfunction and maternal vascular risk factors [122]. The condition of the maternal vasculature is possibly the differentiating factor between those individuals who develop IUGR and those who develop preeclampsia but share the common features of abnormal trophoblast invasion [25,123]. The cardiovascular stress test that is pregnancy, may identify women with an at risk vascular system or with sub-clinical vascular disease [124]. Indeed, conditions with preexisting maternal vascular dysfunction, for example overt hypertension, diabetes, obesity, a previous history of preeclampsia and the presence of coronary artery disease (CAD) risk factors increase the risk for preeclampsia leading to severe early onset disease with greater frequency and also adverse neonatal outcomes [7,125].

Epidemiological studies from 1995 to 2006 show on average a 2-fold increase in either cardiovascular mortality or cardiovascular events after preeclampsia [126–129]. One study reports about a 5-fold increase in the odds ratio for cardiovascular (CV) death if the deliveries were preterm (16–37 weeks) [127]. Women with preeclampsia in addition to having higher rates of heart disease also have higher triglycerides, total cholesterol and low density lipoproteins (LDL) than women with uncomplicated pregnancies [130–133]. The increased risk of developing cardiovascular disease in later life [134] and severe preeclampsia when themselves pregnant [135] in women who were born growth restricted reinforces the concept that preeclampsia and cardiovascular diseases are commonly the result of aberrant vascular functions. Therefore, a constitutional cardiovascular defect is possibly a strong contributory factor in the development of preeclampsia.

Obesity, inflammation and vascular distress

The metabolic adaptations of systemic inflammation, such as oxidative stress, insulin resistance and hyperlipidemia seen in a normal pregnancy are further intensified in preeclampsia [123] and these risk factors are also common to obesity. Obesity and the cluster of pathologies known as metabolic syndrome are growing to epidemic proportions in the world today. Although, obesity has been shown in several studies to be a risk factor for preeclampsia, the mechanisms involved are not known [136]. A common link in both is poor blood flow that causes systemic endothelial dysfunction. The positive correlation between increasing body mass index (BMI) and increased risk of preeclampsia is rather striking, whether it is across a population [137] or it is between pregnancies in the same woman [138]. The central mediator of dysfunction in obesity is the adipose tissue, an endocrine organ wherein activation of inflammatory pathways (JNK and NFκB signaling) resulting in expression of several cytokines such as TNF-α, IL-6 and MCP-1 among several others [139]. Cytokines are also secreted by the placenta and can induce fetal insulin resistance [140]. Adipokines and other inflammation-related proteins are produced both by the placenta and adipocytes [141]. Cellular inflammation in obesity related diseases will impact the vasculature and therefore potentially when combined with pregnancy will lead to even greater inflammatory and oxidative nitrative stress, with a higher risk of placental dysfunction and fetal demise possibly causing preeclampsia.

Endoplasmic reticulum stress

An emerging concept in the area of systemic inflammation and increased apoptosis is endoplasmic reticulum (ER) stress. Obesity may be a chronic stimulus for ER stress in adipose tissue and a central mechanism in triggering insulin resistance and type 2 diabetes [142]. ER stress results in the up regulation of a set of genes encodingGp96, Grp78 and protein disulfide isomerase (PDI), referred to as the unfolded protein response (UPR). Although UPR is considered a survival pathway, prolonged exposure can lead to programmed cell death. We have found the up-regulation of ER stress proteins Gp96 [143] and Grp78 (unpublished data) in the preeclamptic placenta by proteomic profiling studies. Evidence of ER stress has been observed in situations of altered vascular reactivity such as atherosclerotic lesions, neurodegenerative disorders, metabolic syndrome and has been implicated in placental dysfunction [144,145]. It is possible that increased trophoblast apoptosis observed in preeclampsia is a result of prolonged activation of UPR. Although the involvement of ER stress in endothelial dysfunction/injury, a key early step in atherogenesis has been extensively explored, it has been little studied in preeclampsia or in the maternal vasculature.

Conclusion

Our current knowledge of the pathophysiology of preeclampsia is founded on information gleaned from studies involving individuals with established disease. Relative ischemia or hypoxia of the placenta resulting from defective progression of spiral artery remodeling and placental angiogenesis is thought to underlie preeclampsia (see Fig. 2). This placental event is putatively linked to the maternal condition via increased release of antiangiogenic factors sflt-1, endoglin and syncytiotrophoblast membrane fragments into the maternal circulation. These may interact with or damage the maternal vasculature resulting in an inflammatory response and increased maternal vascular resistance and vascular dysfunction in preeclampsia. Heightened oxidative/nitrative stress is seen in the maternal vasculature and particularly in the placenta in preeclampsia. On the basis of both direct in vitro observations and indirect evidence from patients with CAD of alterations in vascular function, induced by nitrative stress, the same may occur in preeclampsia. Any individual’s risk of developing preeclampsia appears to be the result of a variable interaction between placental and maternal vascular systems. The weight of evidence suggests that the cardiovascular stress of pregnancy identifies individuals with preexisting subclinical vascular disease who being unable to withstand that stress then develop preeclampsia. It remains to be shown if development of preeclampsia in an individual with an otherwise normal vasculature is a stimulus for development of cardiovascular disease later in life. Ethical issues obviously limit the ability to perform prospective studies to examine changes in placental and maternal systems that cause subsequent disease. However, there are ongoing studies that will allow measurement of biomarkers for placental and vascular function throughout gestation.

Figure 2.

 Placental and maternal factors interact to develop preeclampsia. Originating in the placenta as a result of reduced trophoblast invasion, ischemia leads to oxidative stress and a continuum of events which adversely affect the maternal vasculature leading to hypertension and proteinuria, that is characteristic of preeclampsia.

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

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