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Preeclampsia, a Disease of the Maternal Endothelium

The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.109.853127Circulation. 2011;123:2856–2869

    Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic.

    Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop.

    Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of women with HELLP syndrome develop disseminated intravascular coagulation, which carries a poor prognosis for both mother and fetus.11 Placental abruption, ascites, hepatic infarction, hepatic rupture, intra-abdominal bleeding, pulmonary edema, and acute renal failure are all severe clinical manifestations associated with preeclampsia that can result in maternal death.13 Perhaps the most feared complication of preeclampsia is eclampsia itself, defined by the presence of seizures, for which women with severe preeclampsia are often treated with magnesium sulfate prophylaxis.1 The brain injury in eclampsia is associated with cerebral edema and characteristic white matter changes of reversible posterior leukoencephalopathy syndrome, which is similar to findings noted in hypertensive encephalopathy and with cytotoxic immunosuppressive therapies.14 Cerebrovascular complications, including stroke and cerebral hemorrhage, are responsible for the majority of eclampsia-related deaths.15 Complications affecting the developing fetus include indicated prematurity,16 intrauterine fetal growth restriction, oligohydramnios, bronchopulmonary dysplasia,17 and increased risk of perinatal death.18

    The risk factors for preeclampsia are varied and unique to this condition. Genetic factors are at least partially responsible, because both a maternal and a paternal family history of the disease predispose to preeclampsia.19 There is a 7-fold risk of recurrence for women who have had the disease in a previous pregnancy.20 Multiple gestation is an additional risk factor, and triplet gestation carries a greater risk than twin, suggesting that increased placental mass plays some role.20 Associations between preeclampsia and nulliparity,20 change in paternity from a previous pregnancy,21 increased interpregnancy interval,22 use of barrier contraception,23 and conception by intracytoplasmic sperm injection24 implicate limited recent exposure to paternal antigen as a predisposing factor. Notably, classic cardiovascular risk factors are associated with preeclampsia: Maternal age >40 years, insulin resistance, obesity, and systemic inflammation and preexisting hypertension, diabetes mellitus, or renal disease all increase the risk.20,25,26 Consistent with this, women with a history of preeclampsia have an elevated risk for cardiovascular disease later in life (see discussion later in this review). Surprisingly, smoking during pregnancy protects against preeclampsia.27

    The diagnosis of preeclampsia is clinical. As defined by the American College of Obstetrics and Gynecology, the diagnosis requires blood pressures >140/90 mm Hg on 2 occasions combined with urinary protein excretion >300 mg/d. Edema, a classic feature of the disease, is no longer considered a diagnostic feature given its lack of sensitivity or specificity.1 Importantly, in 20% of cases, eclampsia may present without preceding hypertension or proteinuria, suggesting that the currently employed diagnostic criteria are imperfect.28 Laboratory tests, such as liver function tests, quantification of urinary protein, and serum creatinine may be helpful in characterizing the degree of end-organ damage, but none is specific for preeclampsia.1 Hyperuricemia, which is more likely to be present in women with preeclampsia than in normotensive pregnant women, has been used as a diagnostic aid and to predict adverse outcomes in preeclampsia, but its predictive value is generally modest.29,30

    Recently, work by our group and others has identified an imbalance of proangiogenic and antiangiogenic proteins as a key factor in the pathogenesis of the preeclampsia.3138 In the present report, we review our current understanding of the biology underlying the disease. We first describe the role of the placenta in preeclampsia, and then review the mechanisms of angiogenesis and its role in preeclampsia and the role of other contributory pathways in the pathogenesis of preeclampsia. Finally, we comment on the potential mechanisms by which the risk of cardiovascular disease is elevated in women with a history of preeclampsia.

    The Preeclamptic Placenta

    The placenta is the central organ in the pathogenesis of preeclampsia. Removal of the placenta abolishes the disease39; moreover, only the placenta, and not the fetus, is required for its development. This is best demonstrated by the case of molar pregnancy, which carries an elevated risk for preeclampsia.40 Pathological examination of placentas from women with severe preeclampsia reveals several abnormalities including infarcts, atherosis, thrombosis, and chronic inflammation.41 It is likely that some of the abnormalities seen in the preeclamptic placenta are consequences of the hypertension and endothelial injury induced by the disease. However, there are abnormalities of placental development that precede the maternal derangements.

    During normal placentation, the embryo-derived cytotrophoblast cells invade the maternal uterine wall. After invasion, cytotrophoblasts are found in the smooth muscle and endothelial layers of the maternal decidual arteries. This interaction acts to induce the remodeling of these maternal vessels into high-capacitance and low-resistance vessels that provide access to maternal oxygen and nutrients for the placenta and developing fetus.42 As part of this process, the cytotrophoblasts adopt an endothelial phenotype, expressing adhesion molecules classically found on the surface of endothelial cells.43 In preeclampsia, this process is aberrant. The invasion of the cytotrophoblasts is incomplete, with cytotrophoblast cells present only in the superficial layers of the decidua.43 The spiral arteries fail to be invaded or remodeled, resulting in constricted, high-resistance vessels, visible on pathological examination of preeclamptic placentas. This shallow invasion has been shown to be related to a failure of the cytotrophoblasts to adopt an endothelial adhesion phenotype44 (Figure 1).

    Figure 1.

    Figure 1. Abnormal placentation in preeclampsia. In normal placental development, invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, transforming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as pseudovasculogenesis, or vascular mimicry (top). In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the spiral arteries is shallow, and they remain small-caliber resistance vessels (bottom). Figure reproduced with permission from Lam et al.45

    Hypoxia may contribute to the aforementioned abnormal placental development because the failure of cytotrophoblasts to fully invade and to switch adhesion molecules can also be reproduced in vitro when cytotrophoblasts are cultured under hypoxic conditions.46 Consistent with this, the risk for preeclampsia is higher in women living at high altitude.47 However, hypoxia resulting from abnormal placentation also contributes to the fetal and maternal complications of the disease. Clinically, abnormal uterine artery Doppler waveforms herald the development of preeclampsia, suggesting decreased placental perfusion.48 Decreased placental perfusion in its more extreme cases results in fetal growth restriction, oligohydramnios, or intrauterine fetal demise. Interestingly, pregnant rats and baboons develop hypertension and proteinuria in response to surgically induced uteroplacental ischemia,49,50 implicating placental hypoxia in the development of the maternal disease.

    Proangiogenic Factors and Vascular Homeostasis

    Abnormalities in the placenta and resulting consequences to the fetus are a hallmark of preeclampsia, but the maternal features of the disease have been its most mysterious feature. Recently, circulating antiangiogenic proteins have been implicated in the pathogenesis of many of the maternal features of the disease (Figure 2). Before describing the manner in which release of these factors into the circulation may lead to the maternal syndrome, we review the evidence for the role of proangiogenic growth factors and their receptors in vascular homeostasis.

    Figure 2.

    Figure 2. sFlt1 and soluble endoglin (sEng) cause endothelial dysfunction by antagonizing vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-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. TβRII indicates transforming growth factor-β type II receptor.

    Vascular Endothelial Growth Factors

    Vascular endothelial growth factors (VEGF) are secreted dimeric glycoproteins involved in vasculogenesis (the process by which new blood vessels are formed in embryonic life) and angiogenesis (the process by which blood vessels branch to form new blood vessels). In humans and other mammals, this family of growth factors includes VEGF-A and placental growth factor (PlGF), among others. VEGF-A (hereafter referred to as VEGF), the first discovered and prototypical protein in this family, is a proangiogenic factor that promotes the proliferation and survival of endothelial cells and induces vascular permeability.51,52 PlGF is a VEGF homolog released by the placenta, which also has proangiogenic activity.53

    Vascular endothelial growth factors family receptors present on vascular endothelial cells include Flt-1 (VEGFR-1) and KDR (VEGFR-2, murine Flk-1). Whereas VEGF binds to both Flt-1 and KDR receptors, PlGF homodimers bind exclusively to Flt-1.54 KDR is thought to be responsible primarily for the action of VEGF on endothelial cells.5557 KDR-null mice die at embryonic day 8.5 to 9.5 with an absence of organized blood vessels and widespread necrosis, suggesting lack of perfusion to vital structures.58 Flt-1–null mice die in embryonic life, with death due to the overgrowth of endothelial cells and resultant blood vessel disarray.58 Mice with Flt-1 lacking the tyrosine kinase domain but with intact ligand binding domain have normal blood vessels and survive,59 implying that Flt-1 acts as a negative regulator of angiogenesis through sequestration of extracellular VEGF rather than through intracellular action. More recently, work by Chappell et al60 suggests that the role of the Flt-1 gene may be to express sFlt-1 (a soluble VEGF signaling inhibitor), which acts by regulating guidance of emerging vessel sprouts by modulating local VEGF availability.

    Vascular endothelial growth factors is essential for embryonic vasculogenesis and angiogenesis. The ablation of a single VEGF allele results in markedly abnormal vasculature, including the placental vasculature, with death at embryonic day 10 to 12.61 Besides its essential role in placental and embryonic vasculogenesis and angiogenesis, VEGF is involved in the survival of endothelial cells and vascular homeostasis in mature vessels and tissues. In adult mice, VEGF is expressed by cell types located adjacent to fenestrated endothelia, including the epithelial cells of the choroid plexus, renal podocytes, and hepatocytes.62 In vitro, VEGF induces endothelial fenestrations,63 whereas inhibition of VEGF in adult mice reduces the density of so-called VEGF-dependent fenestrated capillaries.64 Accordingly, targeted inhibition of VEGF in vivo leads to pathology in many of the organs with fenestrated endothelia, which are also affected in preeclampsia. Specifically, in the mouse kidney, podocyte-selective knockout of VEGF in early postnatal life results in proteinuria, nephrotic syndrome, endotheliosis, and eventual disappearance of endothelial cells from the glomerular tuft, recapitulating the classic renal lesion seen in preeclampsia.65 In the liver, inhibition of VEGF signaling in early postnatal life leads to abnormal liver development, with small hepatocytes and immature sinusoidal vasculature.66 In adult mice, activation of the Flt-1 receptor on liver sinusoidal endothelial cells by VEGF or PlGF leads to elaboration of hepatocyte growth factor and liver enlargement.67 Additionally, in the brain, inhibition of VEGF signaling results in decreased perfusion of choroid plexus vasculature.68

    Vascular endothelial growth factors also seems to have a direct vasodilatory effect on the systemic vasculature because infusion of VEGF leads to nitric oxide–dependent vasorelaxation in the coronary arteries and other vessels in dogs and humans,69 likely through upregulation of nitric oxide and prostacyclin in vascular endothelial cells.70,71 Suggesting a role for VEGF in control of systemic blood pressure, antagonism of the KDR receptor leads to elevations in mean arterial pressure in mice by a nitric oxide–dependent mechanism.72 Most relevant, VEGF inhibition has a biological effect on endothelial function in adult men and women. Side effects of VEGF inhibition in patients undergoing antiangiogenic cancer therapy are consistent with those in animal models, suggesting the homeostatic role of VEGF in the mature vasculature: hypertension, proteinuria, glomerular endothelial damage, hypothyroidism, and, in rare cases, the reversible posterior leukoencephalopathy syndrome.7378

    PlGF, which has ≈53% homology with VEGF, is expressed at high levels by the human placenta. PlGF homodimers do not bind to the KDR receptor but bind to the Flt-1 receptor with high affinity. PlGF has weak mitogenic activity and no effect on vascular permeability in vitro alone but potentiates the actions of VEGF in cultured endothelial cells and in an in vivo vascular permeability model.54 In contrast with VEGF knockout mice, PlGF-null mice have normal vascular development with the exception of subtle defects in the retinal vasculature and in luteal vasculogenesis, which do not seem to affect retinal or reproductive functioning.79 However, PlGF-null mice exhibit defects in tumor angiogenesis, postischemic retinal and myocardial neovascularization, and wound healing, suggesting that PlGF plays a role in angiogenesis in pathological settings.79,80 Consistent with this, PlGF stimulates angiogenesis in ischemic myocardium and arterial collateral growth in ischemic limbs. PlGF may act by displacing VEGF from the Flt-1 receptor, allowing it to bind to the more active KDR receptor.54 Other possible mechanisms include direct effects of Flt-1 signaling and the formation of VEGF/PlGF heterodimers.81,82 During pregnancy, the placenta releases PlGF at high amounts into the maternal circulation. Levels increase beginning in the second trimester, peak during weeks 29 to 32, and decline thereafter. However, because most in vivo investigation of PlGF has been conducted in nonpregnant animals, the function of PlGF in the physiology of normal pregnancy has not been well elucidated.

    Transforming Growth Factor-β

    The transforming growth factor-β (TGF-β) family of proteins is made up of ubiquitous growth factors with diverse actions in many cell types. TGF-β is known to be involved in angiogenesis; however, the mechanisms are not as well elucidated as those in the VEGF pathway. To initiate intracellular signaling, TGF-β and other proteins in this family must bind to both type I and type II receptors on the cell surface. TGF-β isoforms bind the TGF-β type II receptor (TGF-βII) initially with subsequent binding and activation of type I receptors. Mice null for the TGF-βII receptor die at embryonic day 10.5 with defects in hematopoiesis and vasculogenesis,83 implicating TGF-β in the development of the vasculature. Most cell types, including endothelial cells, express the activin-like kinase type I TGF-β receptor ALK5, but endothelial cells alone express ALK1 type I receptor.84 Like TGF-β, ALK1 is important in the development of blood vessels because ALK1-null mice perish by embryonic day 11 to 12 with growth retardation with a markedly reduced number of capillaries and dilation of larger vessels.85 In vitro, TGF-β has differing effects on the activation state of endothelial cells dependent on the dose administered: At low TGF-β doses, ALK1 leads to proliferation and migration of endothelial cells, whereas at high TGF-β doses, ALK5 inhibits proliferation and migration of endothelial cells.84,86 Moreover, TGF-β signaling regulates the expression of VEGF, connecting the 2 pathways and further linking TGF-β to angiogenesis.87

    Transforming growth factor -β signaling in the vasculature also involves coreceptors that act to modulate TGF-β action. Endoglin is a TGF-β coreceptor expressed in endothelial cells and syncytiotrophoblasts of the placenta. Both human endoglin and ALK1 mutations independently cause hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease), characterized by multisystemic vascular malformations.88 Endoglin-null mice die at embryonic day 10 to 12 with abnormal vasculature and internal bleeding.89 On a molecular level, endoglin promotes and is required for TGF-β/ALK1–mediated endothelial cell proliferation and migration.86

    Besides being involved in angiogenesis in the embryonic phase, TGF-β likely functions in vascular homeostasis in mature vessels. In the mouse brain, TGF-β inhibition in combination with VEGF inhibition resulted in the loss of choroid plexus endothelial fenestrae with formation of periventricular edema detectable on magnetic resonance imaging.68 Downregulation of TGF-β signaling in the retinal microvasculature leads to decreased perfusion, breakdown of the blood-retinal barrier, reduced endothelium-dependent vasodilation, and increased endothelial cell apoptosis, suggesting a role for TGF-β in the maintenance of the adult vasculature.90

    Antiangiogenic Factors and Endothelial Dysfunction in Preeclampsia

    In 1989, Roberts and Taylor et al91,92 advanced the hypothesis that preeclampsia results from the release of circulating factors by the placenta, leading to widespread maternal vascular endothelial dysfunction. Several lines of evidence continue to support this understanding of the disease. The cardinal signs and symptoms of preeclampsia involve the vasculature, specifically areas of the vasculature with fenestrated endothelia. Furthermore, vessels isolated from the soft tissue of preeclamptic women demonstrate endothelial dysfunction, with impaired endothelium-dependent but not endothelium-independent dilatation.93,94 Human studies have firmly established the presence of factors released by the injured or activated endothelium in the circulation of women with clinical preeclampsia. These include, among others, endothelin-1,95 fibronectin,9698 von Willebrand factor,96,99 thrombomodulin,100,101 markers of oxidative stress,102 and inflammatory cytokines.103 There is also evidence of deficiency of prostacyclin and nitric oxide, vasodilatory factors released by healthy vasculature, in the circulation of women with preeclampsia.104106 Studies showing that serum from pregnant women with preeclampsia induces endothelial injury and dysfunction in vitro support the theory that a circulating factor causes the aforementioned endothelial dysfunction evident in the disease.92,102,107

    sFlt-1 and PlGF in the Pathogenesis of Preeclampsia

    Because the vascular endothelium relies on proangiogenic factors, the release of antiangiogenic factors by the placenta into the maternal circulation is a plausible cause of the endothelial dysfunction observed in preeclampsia. Investigation by our group and others has characterized 2 such antiangiogenic proteins. Soluble fms-like tyrosine kinase (sFlt-1, also referred to as sVEGFR-1), an antiangiogenic protein, is a soluble form of the VEGF/PlGF receptor Flt-1 produced by alternative splicing.108 sFlt-1 was initially identified as a product of cultured human endothelial cells and subsequently shown to be produced by the placenta and released into the maternal circulation.108110 sFlt-1 is a potent inhibitor of VEGF and PlGF activity: Recombinant sFlt-1 inhibits endothelial tube formation and blocks the vasodilatory effect of VEGF and PlGF in vitro.108 Our group identified elevated expression of sFlt-1 by gene expression profiling in placentas delivered from women with preeclampsia.31 Since that time, several novel sFlt-1 variant isoforms have been identified and shown to be upregulated in preeclampsia.111113

    Animal data support a causal role for sFlt-1 in the pathogenesis of the maternal disease. Administration of sFlt-1 to pregnant rats with the use of an adenoviral vector induced hypertension and proteinuria and caused glomerular endotheliosis, the classic renal lesion seen in preeclampsia.31 Other groups have also generated animal models that implicate sFlt-1 in the pathogenesis of preeclampsia. These include rat and baboon models in which uterine hypoxia induced elevated production of sFlt-1, hypertension, and proteinuria,50,114 as well as a mouse model in which sFlt-1 expression in pregnant females resulted in hypertension, decreased platelet count, and reduced fetal weight.115

    Soluble Endoglin in the Pathogenesis of Preeclampsia

    Notably absent from the phenotype of rats administered sFlt-1 are the liver dysfunction and cerebral changes seen in women with severe preeclampsia. Soluble endoglin (sEng) is another antiangiogenic protein identified by gene expression profiling of placentas from women with preeclampsia. sEng may combine with sFlt-1 to induce features of severe preeclampsia including liver dysfunction, fetal growth restriction, coagulation, and neurological abnormalities.32,68 Our group identified the 65-kDa sEng monomer produced by placentas from preeclamptic women at a level 4-fold higher than placentas from women with normal pregnancies. Subsequent in vitro studies demonstrated that sEng reduces the binding of TGF-β1 to its receptor and blocks TGF-β1–induced vasodilation of rat vessels, likely through downregulation of nitric oxide synthase.32 Furthermore, sEng reduced endothelial tube formation in vitro and led to increased capillary permeability in mouse lung, liver, and kidney. Importantly, when pregnant rats were injected with both sFlt-1 and sEng, a condition reminiscent of severe preeclampsia developed with hypertension, nephrotic range proteinuria, low platelet count, elevated liver enyzmes, and reduced fetal weight.32 Thus, most, if not all, clinical manifestations of preeclampsia can be explained by the antiangiogenic actions of sFlt-1 and sEng on the maternal endothelium. More recent studies have shown that mice injected with both sFlt-1 and sEng expressing adenoviruses, but not those injected with adenoviruses expressing either molecule alone, exhibit not only decreased cerebral perfusion and vascular thrombi but also loss of choroid plexus endothelial fenestrae, choroid plexus endothelial swelling, and cerebral edema on brain magnetic resonance imaging.68 Although women with eclampsia are known to have brain edema and white matter lesions on magnetic resonance imaging, it remains to be seen whether the histopathological changes in women with preeclampsia with neurological involvement are similar to those seen in sFlt-1– and sEng-injected mice.

    Human Studies of sFLT-1, PlGF, and sEng in Preeclampsia

    Epidemiological studies have revealed that blood levels of sFlt-1 and PlGF are altered in women with preeclampsia both during and before clinical signs and symptoms of the disease, consistent with a pathogenic role for these angiogenic factors in preeclampsia. sFlt-1 is present at relatively high concentrations in the serum of normal pregnant women at term116 but declines to nonpregnant levels 48 hours after delivery.31 In preeclampsia, sFlt-1 levels begin to rise at least 5 weeks before the onset of clinical disease and remain elevated compared with unaffected women.34,36,117 Alterations in sFlt1 are more dramatic in patients who have early-onset preeclampsia (preeclampsia at <37 weeks).34 Levels of sFlt-1 also correlate with the severity of the disease.37 In pregnancies afflicted by severe intrauterine fetal growth restriction without preeclampsia, there may also be a modest elevation of sFlt-1 levels.118

    Consistent with the pathophysiology suggested by animal models, levels of free PlGF are depressed in women with preeclampsia. In fact, low PlGF levels in the first trimester, before the sFlt-1 rise, are a risk factor for subsequent preeclampsia.34,119 PlGF can also be measured in the urine of women destined to develop preeclampsia, where levels are depressed compared with normotensive pregnant women beginning at 25 weeks. The degree of suppression of urinary PlGF levels is correlated with the severity of the disease.120 In contrast, although circulating free VEGF levels are low in preeclampsia, it is not useful clinically because the majority of patients have levels below the detection limit of the currently available enzyme-linked immunosorbent assay kits. Of note, the ratio of sFlt-1 to PlGF is a better marker of preeclampsia than either measure alone.121,122 This implies that an imbalance of antiangiogenic and proangiogenic factors rather than the level of either sFlt-1 or PlGF alone leads to preeclampsia.34

    Studies of sEng levels in women with and without preeclampsia are consistent with the animal studies, supporting a role for elevated sEng in the pathogenesis of severe preeclampsia. sEng levels in women with normal pregnancies are stable until approximately week 33 of pregnancy, when they rise, peaking at delivery.33 In women with preeclampsia beginning before 37 weeks of gestation (preterm), levels of sEng begin to rise earlier, by 20 weeks of gestation, and rise more steeply after 33 weeks. Women with preeclampsia beginning after 37 weeks of gestation (term) also have elevated third-trimester sEng levels but a slower rise, beginning at 25 weeks of gestation and rising steeply around 33 weeks of gestation.33 The combination of sFlt-1, PlGF, and sEng levels characterizes preeclampsia better than any single analyte, linking the combined action of several angiogenic factors to clinical preeclampsia.33,123 High circulating levels of both sEng and sFlt-1/PlGF are usually observed before the onset of preterm preeclampsia.33,34 Consistent with this, more recent data suggest that alterations in sFlt-1, PlGF, and sEng in women with preeclampsia are associated with maternal vascular dysfunction and impaired nitric oxide formation.106 In preeclampsia-associated placental abruption, sFlt-1, PlGF, and sEng levels have all been shown to be altered.124,125 In eclampsia, sFlt-1, PlGF, and sEng are also altered to a degree similar to that in patients with severe preeclampsia, reiterating the combined role of these factors in both of these conditions.126

    Other Contributory Factors to the Development of Preeclampsia

    Several factors that are upstream to the angiogenic proteins have been tied to the pathogenesis of preeclampsia (Figure 3). Many of these factors have also been shown to influence sFlt-1 or sEng expression; they may be modulators of their ultimate concentrations in the maternal circulation.

    Figure 3.

    Figure 3. Summary of the pathogenesis of preeclampsia. Angiotensin II Type I Receptor Activating Autoantibodies (AT1-AA), immunologic factors, oxidative stress, and other factors (such as decreased heme oxygenase expression) may cause placental dysfunction, which in turn leads to the release of antiangiogenic factors (such as sFlt1 and soluble endoglin [sEng]) and other inflammatory mediators to induce preeclampsia. NK indicates natural killer; HTN, hypertension.

    Placental Hypoxia

    Because placental hypoxia is thought to be involved in the pathogenesis of preeclampsia (see prior discussion in this review), the effect of hypoxia on sFlt-1 expression has been an area of active investigation. In vitro, culture of cytotrophoblast cells at low oxygen tension has been shown to induce the expression and release of sFlt-1.127,128 sFlt-1 has also been studied in pregnant animal models of preeclampsia in which surgical uteroplacental ischemia is induced and causes hypertension and proteinuria. In both rat114 and baboon,50 surgical uterine ischemia has been shown to induce elevated circulating sFlt-1 levels in addition to the preeclampsia-like syndrome. Overexpression of the stabilized form of hypoxia-inducible factor-1α during mouse pregnancy is associated with a preeclampsia-like phenotype, including elevated levels of sFlt-1 and sEng.129 However, hypoxia studies in animals are associated with enhanced trophoblast invasion,130 suggesting that abnormal placentation is the primary event that leads to placental hypoxia, which in turn may liberate soluble factors necessary for the maternal syndrome.

    Immune Factors

    Risk factors for preeclampsia related to paternal antigen exposure suggest that immunologic dysfunction at the fetal-maternal interface may contribute to preeclampsia. Moreover, women without an intact immune system because of untreated human immunodeficiency virus rarely develop preeclampsia, whereas human immunodeficiency virus treatment and resulting immune reconstitution bring the risk of preeclampsia to levels seen in the general population.131 Normal placentation requires an immune tolerance for fetal antigen, which may be altered in preeclampsia, because pathological examination of preeclamptic placentas reveals increased dendritic cell and macrophage infiltration as well as signs of chronic inflammation.41,132134 Dysregulated complement system has also been proposed as a regulator of placental angiogenesis in animal models.135 Decidual natural killer cells, which promote angiogenesis and are involved in trophoblast invasion, may contribute to the abnormal placental development seen in the disease.136 These cells are further implicated by genetic studies finding associations between polymorphisms in killer immunoglobulin receptors (present on natural killer cells), HLA-C (killer immunoglobulin receptor ligands present on trophoblasts), and preeclampsia.134 These studies provide compelling evidence that immune dysregulation is involved in preeclampsia pathogenesis, but the mechanisms by which this occurs have thus far not been well elucidated.

    Renin-Angiotensin-Aldosterone Pathway

    Normal pregnancy is characterized by resistance to the vasoconstrictive effects of angiotensin II.124 Levels of renin, angiotensin, and aldosterone are increased despite an overall decrease in systemic vascular resistance.137139 In pregnancy-induced hypertension (preeclampsia or gestational hypertension), this resistance is blunted, resulting in increased sensitivity to angiotensin II compared with normotensive pregnant women.124 The fact that circulating angiotensin receptor AT1 activating autoantibody levels are elevated may explain the hypersensitivity to the effects of angiotensin in preeclampsia.140 When injected into pregnant mice, these autoantibodies lead to hypertension, proteinuria, glomerular endothelial damage, and elevated levels of sFlt-1 and sEng and thus may contribute to the pathogenesis of preeclampsia.141 Because in some women with a history of preeclampsia autoantibodies remain elevated, they may also contribute to the development of hypertension in later life.142 Recently, a novel form of circulating oxidized angiotensinogen, which enhances angiotensin formation, has been found in the circulation of preeclamptic subjects.143 However, circulating angiotensin II and aldosterone are suppressed in preeclamptic subjects (and not elevated as one might predict). Studies are needed to evaluate whether this oxidized form of angiotensinogen is altered before clinical disease.

    Alterations in Placental Enzymes

    Recently, genetic knockout of the catechol-O-methyltransferase (COMT) enzyme has been shown to recapitulate some signs and symptoms of preeclampsia.144 COMT knockdown leads to a deficiency of 2-methoxyestradiol, an inhibitor of hypoxia-inducible factor-1α, a transcription factor that acts as a mediator of the cellular response to hypoxia. COMT knockout mice develop placental hypoxia, hypertension, proteinuria, and modestly elevated levels of sFlt-1 in contrast to wild-type mice. Deficiency of 2-methoxyestradiol is also demonstrable in the serum of women with preeclampsia; thus, in some women decreased COMT expression or 2-methoxyestradiol deficiency may be proximal to the elevated levels of sFlt-1.144 Heme oxygenase-1, a placental enzyme whose product is CO, is thought to be a negative regulator of sFlt-1 production. In vitro studies demonstrate that overexpression of heme oxygenase-1 or CO production inhibits sFlt-1 release from placental explants.145 Consistent with these in vitro studies, end-tidal CO levels are lower in women with preeclampsia.146 The suppression of sFlt-1 by CO may also explain the lower risk for preeclampsia in smokers.147

    Oxidative Stress/Placental Debris

    In preeclampsia, oxidative stress is demonstrable both in the placenta and in the maternal circulation.148,149 Preeclamptic placentas produce greater quantities of superoxide and have less antioxidant capacity than normal placentas. Maternal serum from preeclamptic pregnancy shows evidence of oxidative modification of protein and lipoprotein particles. Blood levels of antioxidants have also been reported to be decreased in women with preeclampsia. Unfortunately, large randomized controlled trials did not show an effect of antioxidants vitamin C and vitamin E on the risk of preeclampsia.150154 The shedding of placental debris has also been suggested to cause elevated oxidative stress and endothelial dysfunction in preeclampsia. Placental abnormalities and uteroplacental ischemia may induce the shedding of placental microparticles into the maternal circulation, and these particles may lead to inflammation and vascular damage.155 Consistent with this, women with preeclampsia have elevated circulating levels of placental debris.156,157 Interestingly, these microparticles have been shown to be associated with sFlt-1 in the maternal circulation and thus may be an additional source of circulating sFlt-1 in preeclampsia.158

    Each of these factors may have a role in the regulation and release of antiangiogenic factors into the maternal circulation, but none has been shown to be primarily responsible for the imbalance of angiogenic proteins found in preeclampsia. It is possible that the dysregulation of these factors has multiple etiologies, with overproduction of antiangiogenic factors the final common pathway to preeclampsia. Alternatively, the imbalance in angiogenic proteins may be the primary derangement because angiogenic factors are intimately involved in early placental development (reviewed in Khankin et al159). The regulation of the expression of angiogenic proteins in the placenta is an area of active investigation.

    Implications for Diagnosis and Treatment

    Currently, no laboratory test provides a reliable diagnosis of preeclampsia. This is problematic because hypertension and proteinuria are not specific to preeclampsia, and the treatment for preeclampsia (delivery) puts the preterm fetus at risk. Many women present with “atypical” preeclampsia, without either hypertension or proteinuria, and some of these women go on to have unexpected severe disease.28 Since the initial reports that sFlt-1 may be intimately involved in preeclampsia pathogenesis, several studies have demonstrated the ability of the ratio of sFlt-1 and PlGF to distinguish women with and without preeclampsia with the use of newly developed automated assays with sensitivities and specificities >95% for preterm preeclampsia.121,160,161 Moreover, the measurement of antiangiogenic proteins seems to distinguish preeclampsia in women with chronic diseases who may have hypertension or proteinuria for other reasons, including diabetes mellitus and systemic lupus erythematosus.162,163 Levels of antiangiogenic factors similarly differentiate women with HELLP from women with low platelets due to other conditions including thrombotic thrombocytopenic purpura.164 However, not all patients with preeclampsia have been reported to have altered sFlt1 and PlGF.165 Whether these patients presenting with low levels of sFlt1 and signs/symptoms of preeclampsia represent a nonangiogenic form of the disease or are simply misdiagnosed remains unknown. One possibility is that women with underlying vascular disease may develop preeclamptic signs/symptoms at relatively lower levels of sFlt-1.166 Future prospective studies and clinical trials will define how best to use levels of angiogenic proteins in clinical management. The implication of sFlt-1 in the pathogenesis of preeclampsia also opens the possibility for the development of new targeted therapies. Administration of VEGF rescues the phenotype produced by either sFlt-1 administration167,168 or uterine hypoperfusion in rats,169 suggesting that VEGF itself or compounds that mimic its actions, such as PlGF, may hold promise as treatments for preeclampsia and related conditions. Levels of antiangiogenic factors may also serve as a useful intermediate outcome in initial trials of potential preeclampsia therapies in humans and animals.

    Implications for Later Cardiovascular Disease

    Delivery of the placenta cures preeclampsia, yet affected women continue to have an elevated risk of cardiovascular disease many years postpartum. Large retrospective epidemiological studies have consistently demonstrated an elevated risk for many types of cardiovascular disease in women with a history of preeclampsia.170173 According to a recent meta-analysis, the prevalence of hypertension in women with previous preeclampsia is >50% an average of 14 years after pregnancy, which is 3 to 4 times the risk found in women without preeclampsia.174 Similarly, the risk of death from cardiovascular disease and cerebrovascular disease is ≈2-fold greater in women with a history of preeclampsia. Women who have had preeclampsia before 34 weeks or preeclampsia combined with preterm birth have an even higher risk of death from cardiovascular disease, at 4 to 8 times the risk of women who had a normal pregnancy.172174

    The mechanisms that account for an increased risk of cardiovascular disease in women with a history of preeclampsia are not yet well understood, but endothelial dysfunction, which has been linked to atherosclerosis, persists in formerly preeclamptic women many years after an affected pregnancy. Three months up to at least 3 years postpartum, women with prior preeclampsia demonstrate a decrement in endothelium-dependent dilatation.175 Women with a history of preeclampsia also have been reported to be sensitive to angiotensin II and salt.176 In addition, markers of endothelial activation, including vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, appear to be higher >15 years after pregnancy in women with previous preeclampsia, independent of body mass index and smoking.177 It is possible that shared risk factors may jointly predispose to preeclampsia, endothelial dysfunction, and cardiovascular disease. In this regard, diabetes mellitus, chronic hypertension, and renal disease before pregnancy all confer an elevated risk for preeclampsia. Even subclinical insulin resistance and inflammation, well known to elevate the risk of cardiovascular disease, predispose women to preeclampsia and persist up to 30 years after the disease.16,26,178181 Endothelial dysfunction and cardiovascular disease after preeclampsia may be attributable to these preexisting risk factors and others yet unknown. A recent study of cardiovascular risk factors present before and after pregnancy suggests that nearly half of the elevated risk for future hypertension after preeclampsia can be explained by prepregnancy risk factors.182 Therefore, pregnancy may be viewed as a stress test that can reveal subclinical cardiovascular disease phenotypes long before overt disease (Figure 4) However, further investigation will be necessary to determine whether preeclampsia itself may injure the endothelium and thereby increase the risk of atherosclerosis and cardiovascular disease.

    Figure 4.

    Figure 4. Model for pregnancy as a stress test for long-term cardiovascular disease. This model suggests that the women who develop preeclampsia (red line) have greater underlying vascular risk. This manifests during pregnancy (2 pregnancies are represented) in the form of preeclampsia as well as later in life in the form of hypertension, heart disease, stroke, and other forms of cardiovascular disease. In women without these underlying vascular risk factors (blue line), pregnancy may increase vascular risk slightly but not enough to lead to preeclampsia. These women have a lower cardiovascular risk both during pregnancy and later in life. Adapted from Sattar and Greer183 with permission of the publisher. Copyright © 2002, British Medical Journal.

    Although levels of sFlt-1 decline after delivery of the placenta, a persistent and subtle antiangiogenic milieu may contribute to lasting endothelial dysfunction and an elevated risk of cardiovascular disease in women with a history of preeclampsia. Some176,179 but not all studies35,184,185 have shown that levels of sFlt-1 remained higher in women with a history of preeclampsia compared with those without preeclampsia an average of 18 months postpartum, independent of body mass index, blood pressure, and smoking. The source of sFlt-1 in nonpregnant individuals may be peripheral blood mononuclear cells because monocytes in women with preeclampsia produce elevated levels of sFlt-1 compared with those from control subjects.186,187 Persistent alterations in the levels of antiangiogenic proteins may explain not only the elevated cardiovascular disease risk but also the observed lower risk of malignancy174 and higher risk of acquired hypothyroid function188 in women with a history of preeclampsia. The role of antiangiogenic proteins in the pathophysiology of cardiovascular disease has not been determined. In fact, angiogenesis has been viewed as both a pathogenic and therapeutic factor in cardiovascular disease (reviewed by Khurana et al189). A recent study in 130 patients with chronic kidney disease suggests that elevated levels of sFlt-1 in this group of patients may contribute to endothelial dysfunction and cardiovascular disease risk. Serum from these patients had antiangiogenic activity compared with control serum, which could be attenuated with the administration of an anti-sFlt-1 antibody,187 and sFlt-1 levels were greater in subjects who had a history of myocardial infarction or stroke. Relatively high sFlt-1 levels are also associated with carotid intima-media thickness and progression of atherosclerosis in hypertensive subjects.190 Studies of cardiovascular function and atherogenic potential in animal models expressing high levels of sFlt-1 chronically would add insight in regard to whether antiangiogenic molecules are possible contributors to cardiovascular disease in women. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia have also been described recently; however, the mechanisms mediating these phenotypes are largely unknown.191

    Conclusions

    Preeclampsia is a disease that begins in the placenta and ends at the maternal endothelium. As reviewed here, evidence suggests that the maternal disease is attributable to antiangiogenic factors sFlt-1 and sEng, released by an abnormal placenta. These antiangiogenic factors antagonize the effects of proangiogenic factors VEGF, PlGF, and TGF-β, which are important in the maintenance of the vascular endothelium. Although these antiangiogenic proteins likely cause the maternal disease and may prove to be a useful diagnostic aid, the primary cause of the placental disease is an active area of investigation. Preeclampsia portends future cardiovascular disease, and research into mechanisms by which this increased risk occurs, including the possible role of proangiogenic and antiangiogenic factors, may lead to new insights into the pathogenesis of cardiovascular disease in women.

    Sources of Funding

    C.E.P. is a Howard Hughes Institute Medical Research Training Fellow. Dr Levine receives salary support from the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Karumanchi is supported by the Howard Hughes Medical Institute, an Established Investigator award from the American Heart Association, and a Clinical Scientist award from the Burroughs Wellcome Fund.

    Disclosures

    Dr Karumanchi reports having served as a consultant to Abbott, Beckman Coulter, Roche, and Johnson & Johnson and having been named coinventor on multiple provisional patents filed by Beth Israel Deaconess Medical Center for the use of angiogenesis-related proteins for the diagnosis and treatment of preeclampsia. These patents have been nonexclusively licensed to several companies. Dr Karumanchi reports equity interest in Aggamin LLC. The other authors report no conflicts.

    Footnotes

    Correspondence to S. Ananth Karumanchi, MD,
    Beth Israel Deaconess Medical Center, Center for Vascular Biology, RN 370D, 99 Brookline Ave, Boston, MA 02215
    . E-mail

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