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Am J Physiol Heart Circ Physiol 294: H541-H550, 2008. First published November 30, 2007; doi:10.1152/ajpheart.01113.2007
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INVITED REVIEW

Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction

Jeffrey S. Gilbert, Michael J. Ryan, Babbette B. LaMarca, Mona Sedeek, Sydney R. Murphy, and Joey P. Granger

Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi


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Studies over the last decade have provided exciting new insights into potential mechanisms underlying the pathogenesis of preeclampsia. The initiating event in preeclampsia is generally regarded to be placental ischemia/hypoxia, which in turn results in the elaboration of a variety of factors from the placenta that generates profound effects on the cardiovascular system. This host of molecules includes factors such as soluble fms-like tyrosine kinase-1, the angiotensin II type 1 receptor autoantibody, and cytokines such as tumor necrosis factor-{alpha}, which generate widespread dysfunction of the maternal vascular endothelium. This dysfunction manifests as enhanced formation of factors such as endothelin, reactive oxygen species, and augmented vascular sensitivity to angiotensin II. Alternatively, the preeclampsia syndrome may also be evidenced as decreased formation of vasodilators such as nitric oxide and prostacyclin. Taken together, these alterations cause hypertension by impairing renal pressure natriuresis and increasing total peripheral resistance. Moreover, the quantitative importance of the various endothelial and humoral factors that mediate vasoconstriction and elevation of arterial pressure during preeclampsia remains to be elucidated. Thus identifying the connection between placental ischemia/hypoxia and maternal cardiovascular abnormalities in hopes of revealing potential therapeutic regimens remains an important area of investigation and will be the focus of this review.

kidney; pregnancy; nitric oxide; vascular endothelial growth factor; cytokines

PREECLAMPSIA, a pregnancy-specific syndrome characterized by new onset hypertension and proteinuria, is a considerable obstetric problem and a significant source of maternal and neonatal morbidity and mortality (12, 95). Although preeclampsia and related hypertensive disorders of pregnancy continue to affect ~8% of all pregnancies, the incidence of preeclampsia has seen a 40% increase in recent years (81). Moreover, it has recently been recognized that women who endure preeclampsia are at a greater risk for cardiovascular disease than nonpreeclamptic women and the men who fathered those preeclamptic pregnancies (37). Despite thorough characterization of the preeclamptic syndrome and a suite of contributing circulating factors (12, 77, 80, 95), the mechanisms underlying the pathogenesis of this troubling condition remain nebulous. Interestingly, it has been proposed that not only are increased circulating factors responsible for much of the preeclamptic syndrome, but they may also predispose the maternal cardiovascular system to subsequent endothelial dysfunction as the mother ages (20).

The uncertainties regarding the mechanisms of preeclampsia are at least partially attributable to difficulties faced in the development of suitable animal models for mechanistic research of this disease (72). Consequently, it is held by many that more effective strategies for prevention and treatment of preeclampsia shall be forthcoming with the recent progress in developing animal models that allow careful mechanistic investigation of the underlying pathophysiological mechanisms involved in preeclampsia (32).

Placental Ischemia/Hypoxia and the Etiology of Preeclampsia

Although the pathophysiology of preeclampsia remains undefined, placental ischemia/hypoxia is widely regarded as a key factor (24, 28, 80). Inadequate trophoblast invasion leading to incomplete remodeling of the uterine spiral arteries is considered to be a primary cause of placental ischemia (24). Thus the poorly perfused and hypoxic placenta is thought to synthesize and release increased amounts of vasoactive factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), cytokines, and possibly the angiotensin II (ANG II) type 1 receptor autoantibodies (AT1-AA) (24, 66, 78, 79, 111). Figure 1 illustrates a model by which these and other candidate molecules are thought to induce widespread activation/dysfunction of the maternal endothelium in vessels of the kidney and other organs that ultimately results in hypertension.


Figure 1
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  		Fig. 1. Pathways by which reduced uterine perfusion pressure (RUPP) and placental ischemia may lead to endothelial and cardiovascular dysfunction during pregnancy. Placental ischemia results in increased synthesis of soluble fms-like tyrosine kinase-1 (sFlt-1), TNF-{alpha} and IL-6, angiotensin II type 1 receptor autoantibodies (AT1-AA), and thromboxane (TX). Elevations in these factors are proposed to result in endothelial dysfunction by decreases in bioavailable nitric oxide (NO) and increased reactive oxygen species (ROS) and endothelin-1 (ET-1), which in turn results in altered renal function, increased total peripheral resistance (TPR), and ultimately hypertension. PlGF, placental growth factor.

 
Perhaps the most prominent molecule postulated to play a key role in the pathogenesis of preeclampsia is sFlt-1. Several lines of evidence (15, 41, 42, 47, 50, 51, 74, 93, 103, 104, 117) support the hypothesis that the ischemic placenta contributes to endothelial cell dysfunction in the maternal vasculature by inducing an alteration in the balance of circulating levels of angiogenic/antiangiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sFlt-1. Although recent data suggest that circulating sFlt-1 concentrations may presage the clinical onset of preeclamptic symptoms (47, 51, 75, 106), several studies indicate that placental hypoxia and poor placental perfusion may initiate this imbalance of angiogenic factors (61, 71). Nevertheless, it remains unclear whether impaired placental perfusion initiates preeclamptic symptoms such as hypertension, endothelial dysfunction, and increased sFlt-1 or whether inadequate placental development occurs initially and is followed by a pathological rise in sFlt-1 expression and secretion (41).

Hypertension associated with preeclampsia develops during late pregnancy and remits after delivery or termination of the pregnancy, suggesting that the placenta is a central culprit in the disease. The foremost hypothesis regarding the initiating event in preeclampsia is postulated to be reduced placental perfusion that, in turn, leads to widespread dysfunction of the maternal vascular endothelium. Although numerous other factors including genetic, immunological, behavioral, and environmental influences have been implicated in the pathogenesis of preeclampsia (95, 96), the main focus of this review is to describe the links between placental ischemia/hypoxia and the cardiovascular dysfunction that is widely recognized as a part of the preeclampsia syndrome.

Reduced Uterine Perfusion Pressure as a Model to Study the Pathophysiology of Hypertension During Pregnancy

The physiological mechanisms that mediate the alterations in cardiovascular and renal function that are requisite for a successful pregnancy have been studied in great detail. Nonetheless, experimental data investigating the mechanisms underlying preeclampsia have been limited because of the difficulty in performing mechanistic studies in pregnant women. Although several animal models have been developed to study preeclampsia, none to date completely represents the protean characteristics of the human syndrome. Furthermore, information on the mechanisms mediating the long-term increase in vascular resistance and arterial pressure associated with placental ischemia is lacking.

Experimental induction of chronic uteroplacental ischemia appears to be a promising animal model to study potential mechanisms of preeclampsia since reductions in uteroplacental blood flow in a variety of animals lead to a hypertensive state that has many of the manifestations present in preeclamptic women (5–7, 9–11, 18, 22, 31, 33, 48, 49, 61, 94). It is important to note that the reduced uterine perfusion pressure (RUPP) model of placental ischemia-induced hypertension in pregnancy most closely relates to severe premature/preterm preeclampsia and not late-onset preeclampsia. The former is characterized by intrauterine growth restriction, hypertension, and proteinuria, whereas the latter is not regarded as mediated by placental ischemia and is usually not associated with intrauterine growth restriction. Thus a considerable strength of the RUPP model is that it allows mechanistic investigation of the preterm ischemic placenta and the factors it elaborates.

The relationship between reduced uteroplacental perfusion and hypertension during pregnancy has been demonstrated in a variety of animals, mostly those with hemochorial placentation. Previous studies have shown that chronic RUPP via partial ligation or placement of silver clips on the lower abdominal aorta or uterine arteries results in proteinuric hypertension in the baboon (18, 19, 61), rhesus monkeys (22, 124), rabbit (5, 59), and the dog (6, 35). Our laboratory has established a RUPP model in the pregnant rat (7, 9–11, 31, 33, 48, 49, 94). In this model, uteroplacental perfusion is reduced by ~40% by the placement of silver clips on the aorta and ovarian arteries on day 14 of a 21-day gestation (94). On gestation day 19, the RUPP animals display increased mean arterial pressure (MAP), decreased glomerular filtration rate, decreased renal pressure natriuresis, decreased renal plasma flow and proteinuria, and endothelial dysfunction (7, 9–11, 26, 31, 33, 48, 49). Recently, we demonstrated that these pregnant RUPP rats have increased total peripheral resistance, decreased cardiac index, and decreased uteroplacental blood flow (94), indicating that these animals have marked cardiovascular dysfunction similar to what is observed in preeclamptic women (11a, 17, 94, 109). We have also recently shown that RUPP hypertension in the rat is associated with an imbalance of angiogenic factors, in particular increased sFlt-1 and decreased VEGF and PlGF (30). Thus these models of preeclampsia have many of the features common in preeclamptic women and provide researchers with a valuable substrate from which to investigate the mechanisms of hypertension during pregnancy.

The role of a variety of endothelial, autacoid, and hormonal factors that mediate the cardiovascular and renal dysfunction produced by chronic reductions in uteroplacental perfusion pressure will be the primary focus of the remaining portion of this review. In the present review, we will also focus on the effects of reductions in uteroplacental perfusion pressure on vascular endothelial function since factors that emanate from the ischemic placenta are thought to be responsible for widespread chronic long-term alterations in arterial pressure.

Mediators of Endothelial Dysfunction in Response to Placental Ischemia

The maternal vascular endothelium appears to be an important target of factors that are triggered by placental ischemia/hypoxia in preeclampsia. The endothelium is a single-cell lining that covers the luminal side of blood vessels. This strategic location permits it to signal alterations in hemodynamics and humoral factors by synthesizing and releasing vasoactive substances. Thus a critical balance exists between endothelium-derived relaxing and contracting factors that maintain vascular homeostasis. When this delicate balance is disrupted, the vasculature is predisposed to vasoconstriction, leukocyte adherence, mitogenesis, prooxidation, and vascular inflammation (100, 101). Furthermore, markers of endothelial dysfunction may serve as predictors of the syndrome in women that develop preeclampsia since many are often elevated weeks before observance of clinical manifestations.

Nitric oxide. Substantial evidence indicates that nitric oxide (NO) production is elevated in normal pregnancy and that these increases appear to play an important role in the renal vasodilatation of pregnancy (97). In contrast, the role of NO in preeclampsia remains enigmatic (25, 76, 91).Taken together, these studies underscore the need for continued investigation into the (patho)physiological role of NO in preeclampsia.

Studies from several laboratories indicate that chronic NO synthase inhibition in pregnant rats produces hypertension associated with peripheral and renal vasoconstriction, proteinuria, intrauterine growth restriction, and increased fetal morbidity (23, 43). We have previously reported similar cardiovascular perturbations exist in the NO inhibition and RUPP models, the latter illustrated in Fig. 2 (94). In addition, we have also previously shown that placental ischemia results in the impairment of acetylcholine-mediated vasorelaxation and that nitrite and nitrate productions in aortic strips are both decreased in the RUPP rat compared with normal pregnant rats, shown in Fig. 3 (26). Chronic RUPP in pregnant rats also decreases renal protein expression of neuronal NO synthase but not urinary nitrite/nitrate excretion relative to control pregnant rats (9). Although no difference in urinary nitrite/nitrate excretion was found between RUPP and control pregnant rats, we have found that basal and stimulated release of NO from isolated vascular strips were significantly lower in RUPP rats (13). Although, whether there is a reduction in NO production in this spontaneous model of pregnancy-induced hypertension remains unclear.


Figure 2
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  		Fig. 2. Reduced uterine perfusion pressure elicits increased mean arterial pressure (MAP; A), decreased cardiac index (CI; cardiac output/body weight; B), and increased TPR (C) in late gestation rats. NP, normal pregnant. All data are expressed as means ± SE. *P < 0.05. Graph adapted from Sholook et al. (Ref. 94).

 

Figure 3
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  		Fig. 3. Acetylcholine (ACh)-induced relaxation of vascular strips preconstricted with phenylephrine (3 x 10–7 mol/l) (A) and the basal and ACh-induced nitrite/nitrate production (B) in endothelium-intact aortic strips of NP and RUPP rats. Adapted from Crews et al. (Ref. 26).

 
Oxidative stress. During oxidative stress, an imbalance of pro- and antioxidant factors results in endothelial dysfunction, either by direct actions on the vasculature or through reductions in the bioavailability of vasoactive mediators (113). Oxidative stress may mediate endothelial cell dysfunction and contribute to the pathophysiology of preeclampsia based on evidence of increased prooxidant activity along with decreased antioxidant protection. During preeclampsia, oxidative stress may result from interactions between the maternal component that may include preexisting conditions such as obesity, diabetes, and hyperlipidemia and/or the placental component that may involve secretion of lipid peroxides (79).

Several important antioxidants are significantly decreased in women with preeclampsia. Vitamin C, vitamin A, vitamin E, β-carotene, glutathione levels, and iron-binding capacity are lower in the maternal circulation of women with preeclampsia than in women with a normal pregnancy. Interestingly, supplementation does not appear to ameliorate the incidence of preeclampsia in multicenter clinical trials (73, 83). Reduced superoxide dismutase (SOD) levels and decreased SOD activity have been reported in neutrophils and placentas of women with preeclampsia (113). The decrease in SOD levels and activity in women with preeclampsia is important as diminished SOD occurs within both the maternal and placental components. Consequently, there appears to be a decreased total antioxidant protective capacity in women with preeclampsia.

Experimental data reveal that there is an intimate relationship among reactive oxygen species, NO activity, and blood pressure in rats (85). Thus it is not surprising that there is increased oxidative stress in the hypertensive pregnant RUPP rat (87–89). Whereas antioxidant treatment with vitamins C and E does not decrease blood pressure, the SOD mimetic, Tempol, does attenuate RUPP hypertension (88, 89). Similarly, apocynin, an NADP(H) oxidase inhibitor, attenuates but does not normalize the increased blood pressure observed in RUPP hypertension (89), suggesting that there may be other pathways generating reactive oxygen species in this model. Although oxidative stress is implicated in the pathogenesis of preeclampsia, it remains unclear whether it is a primary or secondary mediator of increased blood pressure and deranged renal function.

Endothelin. Another endothelial-derived factor that may play a role in preeclampsia is the vasoconstrictor endothelin-1 (ET-1) (63, 67, 102). Since endothelial damage is a known stimulus for ET-1 synthesis, increases in the production of endothelin may participate in the pathophysiology of preeclampsia (12). Furthermore, ET-1 is also reported to increase oxidative stress in placental villi (27). Thus endothelin may have additional effects on the maternal cardiovascular system not only by direct actions on the vasculature but also indirectly via oxidative stress.

Previously, we have investigated the role of endothelin in mediating RUPP hypertension in conscious, chronically instrumented pregnant rats (11). Furthermore, we have shown that RUPP elicits increased renal cortical and medullary expression of preproendothelin and that chronic administration of the selective endothelin type A (ETA) receptor antagonist (ABT-627, 5 mg·kg–1·day–1 for 10 days) markedly attenuates the increased mean arterial pressure in these rats (11). In contrast, ETA receptor blockade had no significant effect on blood pressure in the normal pregnant animal, suggesting that ET-1 plays an important role in mediating the hypertension produced by chronic RUPP pregnant rats (11). Furthermore, recent work in our laboratory has shown that sera from pregnant rats exposed to chronic RUPP increase ET-1 production by cultured endothelial cell and that this increase is mediated via the AT1 receptor (82). Although the exact mechanism linking enhanced production of ET-1 to placental ischemia in pregnant rats or in preeclamptic women remains unknown, possibilities include the production of an agonistic AT1-AA and/or increased TNF-{alpha} as we shall describe later.

Arachidonic acid metabolites. Several lines of evidence suggest that changes in the metabolites of arachidonic acid may play a role in mediating the renal dysfunction and increase in arterial pressure during preeclampsia (114). Significant alterations in the balance of prostacyclin and thromboxane production occur in women with preeclampsia (46, 68, 114). Thus, although there is evidence that AA metabolites play a part in preeclampsia, their role is not clearly defined.

Experimental studies in animals have endeavored to determine the role of AA metabolites such as thromboxane in preeclampsia. Such evidence derives from studies indicating that short-term increases in systemic arterial pressure produced by acute RUPP in pregnant dogs can be prevented by thromboxane receptor antagonism (119). Furthermore, we have previously reported that urinary excretion of thromboxane B2 was increased in the RUPP rats compared with normal pregnant rats at day 19 of gestation (56). Additionally, inhibition of cytochrome P-450 enzymes with 1-aminobenzotriazole attenuated the hypertension and increased renal vascular resistance, 20-HETE formation, and cytochrome P-450 4A expression in the renal cortex normally observed in the RUPP rat (55). Nevertheless, experimental data are limited in this area, and the quantitative importance of prostaglandins in mediating long-term reduction in renal hemodynamics and increased arterial pressure produced by chronic RUPP in pregnant rats remains unclear.

Renin-angiotensin system. The renin-angiotensin system (RAS) plays an important role in the long-term regulation of renal function and arterial pressure during a variety of physiological and pathophysiological conditions, and pregnancy and preeclampsia are no exception. During normal pregnancy, plasma renin concentration, renin activity, and ANG II levels are all elevated, yet vascular responsiveness to ANG II appears to be reduced (12, 92). In contrast, during preeclampsia, there appears to be a marked increase in the sensitivity to ANG II (92), although the mechanisms underlying these observations remain unclear.

Recent studies in preeclamptic women have revealed several exciting findings regarding the RAS. AbdAlla and colleagues (1, 2) have shown that the AT1 receptor forms heterodimers with the bradykinin B2 receptor and results in enhanced ANG II sensitivity. Furthermore, these authors (1, 2) have shown that AT1-B2 heterodimers are present in greater abundance in preeclamptic women, suggesting that this heterodimerization may play a part in the long-observed increased ANG II sensitivity in preeclampsia. Another intriguing observation regarding the involvement of the RAS in the pathophysiology of preeclampsia is the demonstration of increased circulating concentrations of an agonistic AT1-AA in preeclamptic women (111, 112). Interestingly, the AT1-AA appear to be responsible for a variety of effects in several different tissues ranging from increased intracellular Ca2+ mobilization to monocyte activation and stimulation of IL-6 production from mesangial cells (16, 99, 115, 120). Another effect that has recently been attributed to the AT1 receptor is stimulation of sFlt-1 expression from trophoblast cells but not endothelial cells via calcineurin signaling (123). Although these findings potentially implicate AT1 as a central mediator of several pathways in preeclampsia, both the specific mechanisms that lead to excess production and the mechanisms whereby AT1-AA increase blood pressure during pregnancy remain unclear. Consequently, this has become an area of intense interest.

Increased vascular responsiveness to ANG II during preeclampsia does not prove it is an important endogenous mediator of vasoconstriction or hypertension in experimental models of preeclampsia since it could merely reflect low endogenous ANG II formation. As such, the importance of increased ANG II to the control of renal function and blood pressure during preeclampsia remains to be determined. Early experiments in our laboratory indicated that chronic oral administration of converting enzyme inhibitor enalapril (250 mg/l for 6 days) decreased MAP to a similar extent in pregnant rats with RUPP and normal pregnant rats, suggesting that the RAS does not play a major role in mediating the hypertension produced by chronic reductions in uterine perfusion pressure in pregnant rats (7). Nevertheless, we have recently found that AT1 receptor antagonism attenuated the blood pressure response to placental ischemia and that RUPP rats have increased circulating levels of the AT1-AA (54). As described in Endothelin and illustrated in Fig. 4, we have also shown that serum from pregnant rats exposed to reductions in uterine perfusion enhances endothelin production by endothelial cells via AT1 receptor activation (82). Although the initial findings by our laboratory and others are exciting, there remains much to be investigated with respect to the manner in which the AT1-AA contribute to the pathophysiology of preeclampsia.


Figure 4
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  		Fig. 4. Effect of losartan, an AT1 receptor antagonist, on medium endothelin concentration after exposure of human umbilical vein endothelial cells to serum from RUPP rats or NP rats. *P < 0.05 vs. control pregnant rats. All data are expressed as means ± SE. Adapted from Roberts et al. (Ref. 82).

 
Cytokines. Several groups have suggested that the etiology of preeclampsia may involve a hypoxia-induced upregulation of placental inflammatory cytokines (24, 78, 116). Although IL-6 and TNF-{alpha} are reportedly elevated in preeclamptic women, the importance of these cytokines in mediating the cardiovascular and renal dysfunction in response to placental ischemia during pregnancy remains unclear. We have previously shown that serum levels of TNF-{alpha} and IL-6 are elevated in RUPP rats and that chronic infusion of TNF-{alpha} (Fig. 5) or IL-6 into pregnant rats at concentrations similar to what is observed in preeclamptic women increases arterial pressure and decreases renal plasma flow and glomerular filtration rate (8, 29, 49). Furthermore, we have found that a low-dose infusion of TNF-{alpha} results in decreased renal neuronal NO synthase expression (8) while also increasing ET-1 mRNA in the kidney, placenta, and vasculature (49). Likewise, we have also reported that ET-1 is complicit in the mediation of this form of pregnancy-induced hypertension since the increased MAP in response to TNF-{alpha} is completely abolished in pregnant rats treated with an ETA receptor antagonist (49). Collectively, these findings suggest that TNF-{alpha}-induced hypertension in pregnant rats is mediated in part by endothlelin, via ETA receptor activation. These studies also suggest that selective ETA receptor antagonists for the treatment of hypertension in women with preeclampsia should receive further attention.


Figure 5
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  		Fig. 5. Changes in MAP in response to TNF-{alpha} infusion and treatment with an endothelin type A (ETA) receptor antagonist in NP rats. (*P < 0.05 vs. NP rats). All data are expressed as means ± SE. Adapted from LaMarca et al. (Ref. 49).

 
Another mechanism by which cytokines may contribute to hypertension during pregnancy is through the modulation of sympathetic nerve activity. Previous studies have shown that women with preeclampsia have increased sympathetic tone (34, 86). Although few studies have examined the effect of specific inflammatory cytokines on blood pressure and the regulation of sympathetic activity, one recent experiment has demonstrated that an acute forebrain infusion of TNF-{alpha} in rats increased arterial pressure, heart rate, and renal sympathetic nerve activity, effects mediated by prostaglandins in the paraventricular nucleus (122). Similarly, another study showed that intracisternal or intravenous infusion of IL-1β increases blood pressure in a prostaglandin-dependent manner in rats (121). Whether chronic elevations in inflammatory cytokines contribute to the increased sympathetic activity during preeclampsia remains to be determined.

Angiogenic factors. Although VEGF is primarily recognized for its potent angiogenic and mitogenic effects on endothelial cells, it has also been recognized as an important contributor to cell homeostasis, in particular with respect to the balance of oxidative stress (3, 4). VEGF exerts its actions mainly by two receptors, VEGF receptor-1 and -2, also known as Flt-1 and the kinase domain region (Flk/KDR), respectively. A soluble and endogenously secreted form of Flt-1 is produced mainly in the placenta by alternative splicing and contains the extracellular ligand-binding domain but not the transmembrane and cytoplasmic portions (21, 44, 45). sFlt-1 disrupts VEGF signaling either by binding VEGF and PlGF or by forming heterodimers with the KDR receptor (45). Although sFlt-1 is not a vasoconstrictor, it does significantly inhibit the dilatory actions of both VEGF and PlGF in vitro, and chronic elevations in circulating concentrations result in increased blood pressure (60, 66). An additional antiangiogenic factor, soluble endoglin (sEng), has also been revealed as a factor in the pathogenesis of preeclampsia (64, 108). Endoglin is a component of the TGF-β receptor complex and is a hypoxia-inducible protein associated with cellular proliferation and NO signaling (38, 52). sEng, on the other hand, has been shown to be antiangiogenic since it is thought to impair TGF-β1 binding to cell surface receptors (38, 108).

Considerable clinical evidence has accumulated that preeclampsia is strongly linked to an imbalance between proangiogenic (VEGF and PlGF) and antiangiogenic (sFlt-1) factors in the maternal circulation (47, 50, 51, 66, 74, 93, 103, 104, 117). Both plasma and amniotic fluid concentrations of sFlt-1 are increased in preeclamptic patients, as well as placental sFlt-1 mRNA (41, 47, 60, 65, 66, 107, 110). Recently, studies have reported that increased sFlt-1 may have a predictive value in diagnosing preeclampsia since concentrations seem to increase before manifestation of overt symptoms (e.g., hypertension and proteinuria) (47, 51). Similarly, recent clinical evidence also suggests that sEng may also presage the onset of preeclampsia (50).

In an elegantly designed study reported several years ago, Maynard et al. (66) reported that exogenous administration of sFlt-1 into pregnant rats via adenovirus-mediated gene transfer resulted in increased arterial pressure and proteinuria and decreased plasma-free VEGF and PlGF concentrations similar to that observed in the preeclamptic patients. The authors (66) also showed that sFlt-1 impaired VEGF- and PlGF-induced vasorelaxation. Subsequently, similar observations using adenovirus transfection have been reported in the mouse (60). Recently, we have developed a model of increased circulating sFlt-1 in pregnant rats using recombinant sFlt-1 delivered via osmotic minipump placed intraperitoneally and found that the dams are hypertensive, have smaller placentae and fetuses, are proteinuric, and show evidence of impaired vascular function on day 18 of gestation (J. P. Granger, unpublished observations). Although these studies have established the importance of sFlt-1 as an important preeclamptic factor, further studies are needed to elucidate mechanisms governing the expression and actions of this protein.

Recently, Li and coworkers (53) showed that VEGF infusion attenuates the increased blood pressure and renal damage observed in pregnant rats overexpressing sFlt-1. Thus, from this study, it can be gleaned that sFlt-1 plays a role in the hypertension and renal dysfunction in preeclampsia; however, these observations did not shed any light on the matter of pathological sFlt-1 overexpression. To this end, we have recently demonstrated that uteroplacental ischemia increased plasma and placental sFlt-1, and this is associated with decreased VEGF and PlGF in the late gestation pregnant rat (30) (Fig. 6). Similarly, Makris and colleagues (61) have reported that uteroplacental ischemia increases sFlt-1 in the baboon as well.


Figure 6
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  		Fig. 6. Plasma concentrations of sFlt-1 (A) were increased in RUPP (n = 18) pregnant rats compared with NP (n = 18) controls at day 19 of pregnancy. Plasma concentrations of VEGF (B) and PlGF (C) were decreased in RUPP (n = 18) pregnant rats compared with NP (n = 18) controls at day 19 of pregnancy. All data are expressed as means ± SE. *P < 0.05. Adapted from Gilbert et al. (Ref. 30).

 
Recent work investigating sEng has furthered progress with respect to the role of antiangiogenic factors in preeclampsia (108). Venkatesha et al. (108) have shown that sEng inhibits in vitro endothelial cell tube formation to a similar extent as sFlt-1. Furthermore, the authors reported in vivo data in the pregnant rat, indicating that an adenovirus-mediated increase of sFlt-1 and sEng in concert exacerbated the effects of either factor alone and resulted in fetal growth restriction, severe hypertension, and nephritic range proteinuria (108). Thus there is compelling experimental evidence that compliments the clinical observations that sEng is an important factor in the pathogenesis of preeclampsia.

Metabolic factors. There are other comorbid conditions that have been proposed as potential contributors to endothelial dysfunction in preeclampsia. Recent studies have indicated a relationship between elements of the metabolic syndrome such as elevated serum triglycerides and free fatty acids (40, 57), insulin resistance (14, 36, 62, 90, 118), and glucose intolerance (39, 98) and the occurrence of preeclampsia. In fact, several authors have suggested that insulin resistance may presage the manifestation of preeclampsia (98, 118), whereas Thadhani et al. (105) have proposed that insulin resistance during pregnancy may collude with other conditions such as impaired angiogenesis to generate a preeclamptic phenotype.

Fatty acids may contribute to endothelial dysfunction by serving as substrates to generate lipid peroxides that are significantly increased in plasma from women with preeclampsia (69). Therefore, the generation of free radicals, lipid peroxides, and reactive oxygen species may be an important mechanism contributing to endothelial dysfunction in preeclampsia (101). Although plasma levels of lipids are increased during normal pregnancy, plasma concentrations of both triglyceride-rich lipoproteins and nonesterified fatty acids are significantly increased in women that develop preeclampsia relative to normal pregnant women (57, 58). This significantly increased plasma triglycerides in women with preeclampsia correlates with an increased plasma of concentrations low-density lipoproteins (84). The nature of this correlative data has provided difficulty in determining a causal effect for abnormal lipid metabolism in the pathogenesis of preeclampsia.

Because there was no definitive data indicating whether or not metabolic derangements were sequelae or potential contributors to placental ischemia, we recently tested this question in our RUPP model. Data obtained from the RUPP model suggest that metabolic derangements similar to the metabolic syndrome X are not a direct consequence of RUPP (31). Rather, it appears that factors associated with metabolic abnormalities may contribute to cardiovascular dysfunction in preeclampsia rather than resulting from poor placental perfusion (31). Further studies are underway to determine what influence obesity may exert during experimental placental ischemia.

Summary

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia remain enigmatic. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles. Placental ischemia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin, thromboxane, and superoxide, increased vascular sensitivity to ANG II, and decreased formation of vasodilators such as NO and prostacyclin. These endothelial abnormalities, in turn, cause hypertension by impairing renal-pressure natriuresis and increasing total peripheral resistance (summarized in Fig. 1). The quantitative importance of the various endothelial and humoral factors in mediating vasoconstriction and increased arterial pressure during preeclampsia remains unclear.

Although recent studies support a role for angiogenic factors, the AT1-AA, cytokines, and other factors as potential mediators of endothelial dysfunction, finding the link between placental ischemia and maternal endothelial and vascular abnormalities remains an important area of investigation. Microarray analysis of genes within the ischemic/hypoxic placenta of women with preeclampsia and in animal models of preeclampsia should provide new insights into novel factors that may provide additional links between placental ischemia/hypoxia and hypertension. More effective strategies for the prevention of preeclampsia should be forthcoming once the underlying pathophysiological mechanisms that are involved in preeclampsia are completely understood.


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This work was supported by National Heart, Lung, and Blood Institute Grants HL-51971, HL-38499, and HL-90269.


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Address for reprint requests and other correspondence: J. P. Granger, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Ctr., 2500 N. State St., Jackson, MS 39216-4505 (e-mail: jgranger{at}physiology.umsmed.edu)


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  1. AbdAlla S, Lother H, el Massiery A, Quitterer U. Increased AT1 receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 7: 1003–1009, 2001.[CrossRef][Web of Science][Medline]
  2. AbdAlla S, Lother H, Quitterer U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407: 94–98, 2000.[CrossRef][Medline]
  3. Abid M, Schoots I, Spokes K, Wu S, Mawhinney C, Aird W. Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and I{kappa}B/NF-{kappa}B. J Biol Chem 279: 44030–44038, 2004.[Abstract/Free Full Text]
  4. Abid M, Tsai J, Spokes K, Deshpande S, Irani K, Aird W. Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. FASEB J 15: 2548–2550, 2001.[Free Full Text]
  5. Abitbol MM, Gallo GR, Pirani CL, Ober WB. Production of experimental toxemia in the pregnant rabbit. Am J Obstet Gynecol 124: 460–470, 1976.[Web of Science][Medline]
  6. Abitbol MM, Pirani CL, Ober WB, Driscoll SG, Cohen MW. Production of experimental toxemia in the pregnant dog. Obstet Gynecol 48: 537–548, 1976.[Web of Science][Medline]
  7. Alexander BT, Cockrell K, Cline FD, Llinas MT, Sedeek M, Granger JP. Effect of angiotensin II synthesis blockade on the hypertensive response to chronic reductions in uterine perfusion pressure in pregnant rats. Hypertension 38: 742–745, 2001.[Abstract/Free Full Text]
  8. Alexander BT, Cockrell KL, Massey MB, Bennett WA, Granger JP. Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression. Am J Hypertens 15: 170–175, 2002.[CrossRef][Web of Science][Medline]
  9. Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF, Bennett WA, Granger JP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension 37: 1191–1195, 2001.[Abstract/Free Full Text]
  10. Alexander BT, Llinas MT, Kruckeberg WC, Granger JP. L-Arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure. Hypertension 43: 832–836, 2004.[Abstract/Free Full Text]
  11. Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA, Granger JP. Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension 37: 485–489, 2001.[Abstract/Free Full Text]
  12. Anonymous. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 163: 1691–1712, 1990.[Web of Science][Medline]
  13. August P, Lindheimer M. Pathophysiology of preeclampsia. In: Hypertension, edited by Laragh J and Brenner BM. New York: Raven, 1995, p. 2407–2426.
  14. Barron LA, Giardina JB, Granger JP, Khalil RA. High-salt diet enhances vascular reactivity in pregnant rats with normal and reduced uterine perfusion pressure. Hypertension 38: 730–735, 2001.[Abstract/Free Full Text]
  15. Bartha J, Romero-Carmona R, Torrejon-Cardoso R, Comino-Delgado R. Insulin, insulin-like growth factor-1, and insulin resistance in women with pregnancy-induced hypertension. Am J Obstet Gynecol 187: 735–740, 2002.[CrossRef][Web of Science][Medline]
  16. Bdolah Y, Sukhatme VP, Karumanchi SA. Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights. Semin Nephrol 24: 548–556, 2004.[Web of Science][Medline]
  17. Bobst SM, Day MC, Gilstrap LC 3rd, Xia Y, Kellems RE. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion. Am J Hypertens 18: 330–336, 2005.[CrossRef][Web of Science][Medline]
  18. Bosio P, Mckenna P, Conroy R, O'Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol 94: 978–984, 1999.[CrossRef][Web of Science][Medline]
  19. Cavanagh D, Rao PS, Tsai CC, O'Connor TC. Experimental toxemia in the pregnant primate. Am J Obstet Gynecol 128: 75–85, 1977.[Web of Science][Medline]
  20. Cavanagh D, Rao PS, Tung KS, Gaston L. Eclamptogenic toxemia: the development of an experimental model in the subhuman primate. Am J Obstet Gynecol 120: 183–196, 1974.[Web of Science][Medline]
  21. Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS. Association of maternal endothelial dysfunction with preeclampsia. JAMA 285: 1607–1612, 2001.[Abstract/Free Full Text]
  22. Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AN, Lammoglia R, Charnock-Jones DS. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 59: 1540–1548, 1998.[Abstract/Free Full Text]
  23. Combs CA, Katz MA, Kitzmiller JL, Brescia RJ. Experimental preeclampsia produced by chronic constriction of the lower aorta: validation with longitudinal blood pressure measurements in conscious rhesus monkeys. Am J Obstet Gynecol 169: 215–223, 1993.[Web of Science][Medline]
  24. Conrad KP. Animal models of pre-eclampsia: do they exist? Fetal Medicine Review 2: 67–88, 1990.[CrossRef]
  25. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol 37: 240–249, 1997.[Web of Science][Medline]
  26. Conrad KP, Kerchner LJ, Mosher MD. Plasma and 24-h NOx and cGMP during normal pregnancy and preeclampsia in women on a reduced NOx diet. Am J Physiol Renal Physiol 277: F48–F57, 1999.[Abstract/Free Full Text]
  27. Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. Hypertension 35: 367–372, 2000.[Abstract/Free Full Text]
  28. Fiore G, Florio P, Micheli L, Nencini C, Rossi M, Cerretani D, Ambrosini G, Giorgi G, Petraglia F. Endothelin-1 triggers placental oxidative stress pathways: putative role in preeclampsia. J Clin Endocrinol Metab 90: 4205–4210, 2005.[Abstract/Free Full Text]
  29. Fisher SJ, Roberts JM. Defects in placentation and placental perfusion. In: Chelsey's Hypertensive Disorders in Pregnancy, edited by Lindheimer MD, Roberts JM, and Cunningham FG. Stanford, CT: Appleton & Lange, 1999, p. 377–394.
  30. Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension 48: 711–716, 2006.[Abstract/Free Full Text]
  31. Gilbert JS, Babcock SA, Granger JP. Hypertension produced by reduced uterine perfusion pressure in pregnant rats is associated with increased soluble sFlt-1 expression. Hypertension 50: 1142–1147, 2007.[Abstract/Free Full Text]
  32. Gilbert JS, Dukes M, LaMarca BB, Cockrell K, Babcock SA, Granger JP. Effects of reduced uterine perfusion pressure on blood pressure and metabolic factors in pregnant rats. Am J Hypertens 20: 686–691, 2007.[CrossRef][Web of Science][Medline]
  33. Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens 14: 178S–185S, 2001.[CrossRef][Web of Science][Medline]
  34. Granger JP, LaMarca BB, Cockrell K, Sedeek M, Balzi C, Chandler D, Bennett W. Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. Methods Mol Med 122: 383–392, 2006.[Medline]
  35. Greenwood JP, Scott EM, Stoker JB, Walker JJ, Mary DA. Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans. Circulation 104: 2200–2204, 2001.[Abstract/Free Full Text]
  36. Hodari AA. Chronic uterine ischemia and reversible experimental "toxemia of pregnancy." Am J Obstet Gynecol 97: 597–607, 1967.[Web of Science][Medline]
  37. Innes KE, Wimsatt JH, McDuffie R. Relative glucose tolerance and subsequent development of hypertension in pregnancy. Obstet Gynecol 97: 905–910, 2001.[CrossRef][Web of Science][Medline]
  38. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long-term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 323: 1213–1217, 2001.[Abstract/Free Full Text]
  39. Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F, Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-Novoa JM. Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J 18: 609–611, 2004.[Abstract/Free Full Text]
  40. Joffe G, Esterlitz J, Levine R, Clemens J, Ewell M, Sibai B, Catalano P. The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Am J Obstet Gynecol 179: 1032–1037, 1998.[CrossRef][Web of Science][Medline]
  41. Kaaja R, Tikkanen MJ, Viinikka L, Ylikorkala O. Serum lipoproteins, insulin, and urinary prostanoid metabolites in normal and hypertensive pregnant women. Obstet Gynecol 85: 353–356, 1995.[CrossRef][Web of Science][Medline]
  42. Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the "chicken-and-egg" question. Endocrinology 145: 4835–4837, 2004.[Free Full Text]
  43. Karumanchi SA, Maynard SE, Stillman IE, Epstein FH, Sukhatme VP. Preeclampsia: a renal perspective. Kidney Int 67: 2101–2113, 2005.[CrossRef][Web of Science][Medline]
  44. Kassab S, Miller MT, Hester R, Novak J, Granger JP. Systemic hemodynamics and regional blood flow during chronic nitric oxide synthesis inhibition in pregnant rats. Hypertension 31: 315–320, 1998.[Abstract/Free Full Text]
  45. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogeneously encoded soluble receptor. Proceed Natl Acad Sci USA 90: 10705–10709, 1993.[Abstract/Free Full Text]
  46. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226: 324–328, 1996.[CrossRef][Web of Science][Medline]
  47. Klockenbusch W, Goecke TW, Krüssel JS, Tutschek BA, Crombach G, Schrör K. Prostacyclin deficiency and reduced fetoplacental blood flow in pregnancy-induced hypertension and preeclampsia. Gynecol Obstet Invest 50: 103–107, 2000.[CrossRef][Web of Science][Medline]
  48. Lam C, Lim KH, Karumanchi SA. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46: 1077–1085, 2005.[Abstract/Free Full Text]
  49. LaMarca BB, Bennett WA, Alexander BT, Cockrell K, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of tumor necrosis factor-alpha. Hypertension 46: 1022–1025, 2005.[Abstract/Free Full Text]
  50. LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. Hypertension 46: 82–86, 2005.[Abstract/Free Full Text]
  51. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355: 992–1005, 2006.[Abstract/Free Full Text]
  52. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350: 672–683, 2004.[Abstract/Free Full Text]
  53. Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C, Kumar S. CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci 116: 2677–2685, 2003.[Abstract/Free Full Text]
  54. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, O'Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 50: 686–692, 2007.[Abstract/Free Full Text]
  55. Llinas M, Wallukat G, Dechend R, Mueller DN, Luft FC, Alexander BT, LaMarca B, Granger JP. Agonistic autoantibodies to the AT1 receptor in a rat model of preeclampsia induced by chronic reductions in uterine perfusion pressure (RUPP) (Abstract). Hypertension 46: 884, 2005.
  56. Llinas MT, Alexander BT, Capparelli MF, Carroll MA, Granger JP. Cytochrome P-450 inhibition attenuates hypertension induced by reductions in uterine perfusion pressure in pregnant rats. Hypertension 43: 623–628, 2004.[Abstract/Free Full Text]
  57. Llinas MT, Alexander BT, Seedek M, Abram SR, Crell A, Granger JP. Enhanced thromboxane synthesis during chronic reductions in uterine perfusion pressure in pregnant rats. Am J Hypertens 15: 793–797, 2002.[CrossRef][Web of Science][Medline]
  58. Lorentzen B, Drevon CA, Endresen MJ, Henriksen T. Fatty acid pattern of esterified and free fatty acids in sera of women with normal and pre-eclamptic pregnancy. Br J Obstet Gynaecol 102: 530–537, 1995.[Web of Science][Medline]
  59. Lorentzen B, Henriksen T. Plasma lipids and vascular dysfunction in preeclampsia. Semin Reprod Endocrinol 16: 33–39, 1998.[Web of Science][Medline]
  60. Losonczy G, Brown G, Venuto RC. Increased peripheral resistance during reduced uterine perfusion pressure hypertension in pregnant rabbits. Am J Med Sci 303: 233–240, 1992.[Web of Science][Medline]
  61. Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD, Hankins GD, Saade GR. The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol 196: e1–e7, 2007.[Medline]
  62. Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int 71: 977–984, 2007.[CrossRef][Web of Science][Medline]
  63. Martinez Abundis E, Gonzalez Ortiz M, Quiñones Galvan A, Ferrannini E. Hyperinsulinemia in glucose-tolerant women with preeclampsia. A controlled study. Am J Hypertens 9: 610–614, 1996.[CrossRef][Web of Science][Medline]
  64. Mastrogiannis DS, O'Brien WF, Krammer J, Benoit R. Potential role of endothelin-1 in normal and hypertensive pregnancies. Am J Obstet Gynecol 165: 1711–1716, 1991.[Web of Science][Medline]
  65. Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correlation between soluble endoglin, vascular endothelial growth factor receptor-1, and adipocytokines in preeclampsia. J Clin Endocrinol Metab 92: 2672–2679, 2007.[Abstract/Free Full Text]
  66. Maynard SE, Venkatesha S, Thadhani R, Karumanchi SA. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res 57: 1R–7R, 2005.[CrossRef][Web of Science][Medline]
  67. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658, 2003.[CrossRef][Web of Science][Medline]
  68. McMahon LP, Redman CW, Firth JD. Expression of the three endothelin genes and plasma levels of endothelin in pre-eclamptic and normal gestations. Clin Sci (Lond) 85: 417–424, 1993.[Medline]
  69. Mills JL, DerSimonian R, Raymond E, Morrow JD, Roberts LJ, Clemens JD, Hauth JC, Catalano P, Sibai B, Curet LB, Levine RJ. Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: a multicenter prospective study. JAMA 282: 356–362, 1999.[Abstract/Free Full Text]
  70. Murai JT, Muzykanskiy E, Taylor RN. Maternal and fetal modulators of lipid metabolism correlate with the development of preeclampsia. Metabolism 46: 963–967, 1997.[CrossRef][Web of Science][Medline]
  71. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A, Zamudio S, Caniggia I. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 291: R1085–R1093, 2006.[Abstract/Free Full Text]
  72. Podjarny E, Losonczy G, Baylis C. Animal models of preeclampsia. Semin Nephrol 24: 596–606, 2004.[Web of Science][Medline]
  73. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 367: 1145–1154, 2006.[CrossRef][Web of Science][Medline]
  74. Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA, Karumanchi SA, Thadhani R, Wolf M, Harger G, Markovic N. Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta 26: 563–573, 2005.[CrossRef][Web of Science][Medline]
  75. Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Tamez H, Thadhani R. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension 50: 137–142, 2007.[Abstract/Free Full Text]
  76. Ranta V, Viinikka L, Halmesmaki E, Ylikorkala O. Nitric oxide production with preeclampsia. Obstet Gynecol 93: 442–445, 1999.[CrossRef][Web of Science][Medline]
  77. Redman CW. Current topic: pre-eclampsia and the placenta. Placenta 12: 301–308, 1991.[Web of Science][Medline]
  78. Rinehart BK, Terrone DA, Lagoo-Deenadayalan S, Barber WH, Hale EA, Martin JN Jr, Bennett WA. Expression of the placental cytokines tumor necrosis factor alpha, interleukin 1beta, and interleukin 10 is increased in preeclampsia. Am J Obstet Gynecol 181: 915–920, 1999.[CrossRef][Web of Science][Medline]
  79. Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens 4: 700–708, 1991.[Web of Science][Medline]
  80. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 161: 1200–1204, 1989.[Web of Science][Medline]
  81. Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the NHLBI working group on research on hypertension during pregnancy. Hypertension 41: 437–445, 2003.[Abstract/Free Full Text]
  82. Roberts L, LaMarca BB, Fournier L, Bain J, Cockrell K, Granger JP. Enhanced endothelin synthesis by endothelial cells exposed to sera from pregnant rats with decreased uterine perfusion. Hypertension 47: 615–618, 2006.[Abstract/Free Full Text]
  83. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS, the Study Group ACTS. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 354: 1796–1806, 2006.[Abstract/Free Full Text]
  84. Sattar N, Greer IA, Louden J, Lindsay G, McConnell M, Shepherd J, Packard CJ. Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein. J Clin Endocrinol Metab 82: 2483–2491, 1997.[Abstract/Free Full Text]
  85. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in shr with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 32: 59–64, 1998.[Abstract/Free Full Text]
  86. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia—a state of sympathetic overactivity. N Engl J Med 335: 1480–1485, 1996.[Abstract/Free Full Text]
  87. Sedeek MH, Alexander BT, Sholook MM, Chandler DL, Abram SR, Granger JP. Renal cortical NADPH oxidase and superoxide dismutase activity in response to reduced uterine perfusion pressure in pregnant rats (Abstract). FASEB J 18: A740, 2004.
  88. Sedeek MH, Sholook MM, Blazli C, Abram SR, Chandler DL, Granger JP. Tempol, but not vitamin E & C, decreases the blood pressure response to a chronic reduction in uterine perfusion pressure in pregnant rats (Abstract). FASEB J 18: A740, 2004.
  89. Sedeek MH, Wang YP, Granger JP. Increased oxidative stress in a rat model of preeclampsia (Abstract). Am J Hypertens 17: 142A, 2004.
  90. Seely EW, Solomon CG. Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab 88: 2393–2398, 2003.[Abstract/Free Full Text]
  91. Shaamash AH, Elsnosy ED, Makhlouf AM, Zakhari MM, Ibrahim OA, El-Dien HM. Maternal and fetal serum nitric oxide (NO) concentrations in normal pregnancy, pre-eclampsia and eclampsia. Int J Gynaecol Obstet 68: 207–214, 2000.[CrossRef][Medline]
  92. Shah DM. Role of the renin-angiotensin system in the pathogenesis of preeclampsia. Am J Physiol Renal Physiol 288: F614–F625, 2005.[Abstract/Free Full Text]
  93. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab 90: 4895–4903, 2005.[Abstract/Free Full Text]
  94. Sholook MM, Gilbert JS, Sedeek MH, Huang M, Hester RL, Granger JP. Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats. Am J Physiol Heart Circ Physiol 293: H2080–H2084, 2007.[Abstract/Free Full Text]
  95. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 365: 785–799, 2005.[Web of Science][Medline]
  96. Sibai B, Ewell M, Levine R, Klebanoff M, Esterlitz J, Catalano P, Goldenberg R, Joffe G. Risk factors associated with preeclampsia in healthy nulliparous women. Am J Obstet Gynecol 177: 1003–1010, 1997.[CrossRef][Web of Science][Medline]
  97. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol Regul Integr Comp Physiol 272: R441–R463, 1997.[Abstract/Free Full Text]
  98. Solomon CG, Graves SW, Greene MF, Seely EW. Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 23: 717–721, 1994.[Abstract/Free Full Text]
  99. Stepan H, Faber R, Wessel N, Wallukat G, Schultheiss HP, Walther T. Relation between circulating angiotensin II type 1 receptor agonistic autoantibodies and soluble fms-like tyrosine kinase 1 in the pathogenesis of preeclampsia. J Clin Endocrinol Metab 91: 2424–2427, 2006.[Abstract/Free Full Text]
  100. Taylor RN, Roberts JM. Endothelial cell dysfunction. In: Chelsey's Hypertensive Disorder's of Pregnancy, edited by Lindheimer M, Roberts JM, and Cunningham FG. Stanford, CT: Appleton & Lange, 2007, p. 395–429.
  101. Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol 16: 17–31, 1998.[Web of Science][Medline]
  102. Taylor RN, Varma M, Teng NN, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab 71: 1675–1677, 1990.[Abstract/Free Full Text]
  103. Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 89: 770–775, 2004.[Abstract/Free Full Text]
  104. Thadhani RI, Johnson RJ, Karumanchi SA. Hypertension during pregnancy: a disorder begging for pathophysiological support. Hypertension 46: 1250–1251, 2005.[Free Full Text]
  105. Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme VP, Levine RJ, Karumanchi SA. Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. Hypertension 43: 988–992, 2004.[Abstract/Free Full Text]
  106. Tranquilli AL, Bezzeccheri V, Giannubilo SR, Scagnoli C, Mazzanti L, Garzetti GG. Amniotic vascular endothelial growth factor (VEGF) and nitric oxide (NO) in women with subsequent preeclampsia. Eur J Obstet Gynecol Reprod Biol 113: 17–20, 2004.[CrossRef][Web of Science][Medline]
  107. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, Schaaps JP, Cabrol D, Frankenne F, Foidart JM. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 88: 5555–5563, 2003.[Abstract/Free Full Text]
  108. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12: 642–649, 2006.[CrossRef][Web of Science][Medline]
  109. Visser W, Wallenburg HC. Central hemodynamic observations in untreated preeclamptic patients. Hypertension 17: 1072–1077, 1991.[Abstract/Free Full Text]
  110. Vuorela P, Helske S, Hornig C, Alitalo K, Weich H, Halmesmaki E. Amniotic fluid-soluble vascular endothelial growth factor receptor-1 in preeclampsia. Obstet Gynecol 95: 353–357, 2000.[CrossRef][Web of Science][Medline]
  111. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jupner A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H, Luft FC. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103: 945–952, 1999.[Web of Science][Medline]
  112. Wallukat G, Neichel D, Nissen E, Homuth V, Luft FC. Agonistic autoantibodies directed against the angiotensin II AT1 receptor in patients with preeclampsia. Can J Physiol Pharmacol 81: 79–83, 2003.[CrossRef][Web of Science][Medline]
  113. Walsh SW. Maternal-placental interactions of oxidative stress and antioxidants in preeclampsia. Semin Reprod Endocrinol 16: 93–104, 1998.[Web of Science][Medline]
  114. Walsh SW. Eicosanoids in preeclampsia. Prostaglandins Leukot Essent Fatty Acids 70: 223–232, 2004.[CrossRef][Web of Science][Medline]
  115. Walther T, Wallukat G, Jank A, Bartel S, Schultheiss HP, Faber R, Stepan H. Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature. Hypertension 46: 1275–1279, 2005.[Abstract/Free Full Text]
  116. Wang Y, Walsh SW. TNF alpha concentrations and mRNA expression are increased in preeclamptic placentas. J Reprod Immunol 32: 157–169, 1996.[CrossRef][Web of Science][Medline]
  117. Wolf M, Shah A, Lam C, Martinez A, Smirnakis KV, Epstein FH, Taylor RN, Ecker JL, Karumanchi SA, Thadhani R. Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies. Am J Obstet Gynecol 193: 16–22, 2005.[CrossRef][Web of Science][Medline]
  118. Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 87: 1563–1568, 2002.[Abstract/Free Full Text]
  119. Woods LL. Importance of prostaglandins in hypertension during reduced uteroplacental perfusion pressure. Am J Physiol Regul Integr Comp Physiol 257: R1558–R1561, 1989.[Abstract/Free Full Text]
  120. Xia Y, Wen H, Bobst S, Day MC, Kellems RE. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig 10: 82–93, 2003.[CrossRef][Web of Science][Medline]
  121. Ye S, Mozayeni P, Gamburd M, Zhong H, Campese VM. Interleukin-1beta and neurogenic control of blood pressure in normal rats and rats with chronic renal failure 1. Am J Physiol Heart Circ Physiol 279: H2786–H2796, 2000.[Abstract/Free Full Text]
  122. Zhang ZH, Wei SG, Francis J, Felder RB. Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins 1. Am J Physiol Regul Integr Comp Physiol 284: R916–R927, 2003.[Abstract/Free Full Text]
  123. Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, Sun C, Ahmed A, Kellems RE, Xia Y. Angiotensin II induces soluble fms-like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res 100: 88–95, 2007.[Abstract/Free Full Text]
  124. Zhou Y, Chiu K, Brescia RJ, Combs CA, Katz MA, Kitzmiller JL, Heilbron DC, Fisher SJ. Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys. Am J Obstet Gynecol 169: 224–229, 1993.[Web of Science][Medline]



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