Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Ther Adv Cardiovasc Dis. Author manuscript; available in PMC Oct 1, 2009.
Published in final edited form as:
PMCID: PMC2692864

Systemic and uteroplacental renin–angiotensin system in normal and pre-eclamptic pregnancies


Pregnancy is characterized by an increase in many of the different components of the circulating renin–angiotensin system [RAS]. However, the physiological mechanisms of stimulated RAS activity during pregnancy are unknown. Even less understood is how this system may be altered in pre-eclampsia, a hypertensive disorder of pregnancy. Additional studies have shown the presence of a local tissue specific RAS in the uteroplacental unit of normal and pre-eclamptic pregnancies. Differences in normal pregnant and pre-eclamptic RAS component regulation may provide insight into the mechanisms responsible for the clinical pathological features of pre-eclampsia. Specifically, this review summarizes the key findings in the circulating and uteroplacental RAS in normal and pre-eclamptic pregnancies.

Keywords: pregnancy, pre-eclampsia, placenta, uterus, renin-angiotensin system, angiotensin II, angiotensin-[1-7]

Hypertensive disorders of pregnancy

Despite extensive research, hypertensive disorders of pregnancy continue to be the second leading cause, behind embolism, of maternal mortality in the US accounting for almost 15% of such deaths [Working Group on High Blood Pressure in Pregnancy, 1991]. Hypertensive disorders are one of the most common medical complications of pregnancy, affecting 7–10% of all pregnancies and contributing significantly to still-births and neonatal morbidity and mortality [The Working Group on High Blood Pressure in Pregnancy, 1991]. Approximately 70% of hypertensive disorders of pregnancy are due to gestational hypertension which includes pre-eclampsia and eclampsia [Moldenhauer and Sibai, 2003). Therefore, the prevention of hypertensive disorders of pregnancy, including pre-eclampsia, would have a significant impact on maternal and neonatal outcome.

Unfortunately, although some of the predisposing risk factors of pre-eclampsia have been identified, there is still no proven preventative therapy. In addition, there are no predictive tests and the only known cure for pre-eclampsia is delivery, which often occurs prematurely. The ability to prevent pre-eclampsia is limited due to the fact that its pathophysiology remains poorly understood.

Pathophysiology of normal pregnancy and pre-eclampsia

During normal pregnancy, immediately following implantation, cytotrophoblast cells of embryonic origin undergo a process termed pseudovasculogenesis whereby these cells change from an epithelial to an endothelial phenotype [Zhou et al. 1997b]. This change occurs mostly through a decrease in epithelial cell specific adhesion receptors such as integrin α6β4 and E-cadherin and the onset of expression of adhesion receptors characteristic of endothelium such as VE (vascular) -cadherin, vascular cell adhesion molecule (VCAM-1), platelet-endothelial cell adhesion molecule (PECAM-1), and integrins αVβ3 and α1β1 [Zhou et al. 1997b; Vicovac et al. 1995; Damsky et al. 1992]. The functional consequence of this change in cell phenotype is to allow the cytotrophoblasts to invade the maternal uterine spiral arteries where they completely replace the endothelial layers of these vessels. The remodeling of the uterine spiral arteries causes the vessels to increase in diameter allowing for an increase in blood flow into the intervillous space of the placenta permitting normal gas and nutrient exchange and healthy growth of the fetus. However, previous studies have shown that women with pre-eclampsia undergo abnormal pseudovasculogenesis causing the invasion of the maternal uterine spiral arteries to be shallow and very limited [Zhou et al. 1997a], Consequently, the diameter of these vessels remains narrow and undilated preventing normal amounts of oxygenated blood from reaching the placenta. The placenta then becomes increasingly hypoxic as gestation progresses. The ischemic placenta will then release factors that cause endothelial cell activation and/or dysfunction resulting in vasoconstriction, abnormal angiogenesis, and the end organ damage seen in the mother including the pathologic hallmarks of pre-eclampsia – hypertension, proteinuria and edema. Although this is the current hypothesis for the overall cause of pre-eclampsia, there are still many unanswered questions regarding the specific molecular pathways altered in this disease.

Renin–angiotensin system components

The renin–angiotensin system (RAS) is known to be an important regulator of blood pressure, sodium and fluid homeostasis. In non-pregnant models, RAS activity is enhanced causing hypertension [Laragh, 1992; MacGregor et al. 1981], salt retention [Hall and Brands, 1992; Hall et al. 1992], and hyperaldosteronism [Gordon et al. 1992; Bravo et al. 1977; Genest et al. 1977]. Angiotensinogen, the precursor of the formation of the angiotensin peptides, is converted to the inactive decapeptide, angiotensin I (Ang I), by an aspartyl protease, renin. Angiotensin converting enzyme (ACE: EC is the major enzyme responsible for the formation of the vasoconstrictor peptide angiotensin II (Ang II) from Ang I. ACE is a metalloprotease that releases C-terminal dipeptides from substrates such as Ang I and bradykinin (BK) [Welches et al. 1993] and ACH was recently shown to degrade angiotensin-(1-7) [Ang-(1-7)] [Allred et al. 2000]. Ang-(1-7) is generated from either Ang I or Ang II by specific peptidases [Brosnihan et al. 1988; Ferrario and Chappell, 1994], Ang-(1–7) is formed from Ang I by neprilysin (NEP 224.11), thimet oligopeptidase (EC 25.15), and prolyl oligopeptidase (EC 24.26) [Ferrario and Chappell, 1994; Brosnihan et al. 1988]. Angiotensin-converting enzyme 2 (ACE2), a new member of the RAS pathway, can cleave a single residue from Ang II to form Ang-(1-7). ACE2 is a carboxypeptidase drat has a 42% homology with ACE, but displays different biological activities from ACE. ACE2 can cleave one ammo acid from Ang I to generate angiotensin-(1-9) [Ang-(1-9)] which can be further processed into Ang-(1-7) by neprilysin and ACE [Vickers et al. 2002]. The catalytic efficiency of ACE2 for generating Ang-(1-7) from Ang II is almost 500-fold greater than that for the conversion of Ang I to Ang-(1-9) and 10- to 600-fold higher than that of prolyl oligopeptidase and prolyl carboxypeptidase, respectively, to form Ang-(1-7) [Vickers et al. 2002]. Data suggest that ACE2 may act to counter-regulate the activity of the vasoconstrictor components of the RAS [Brosnihan et al. 2004, 2003; Bricca, 2002; Crackower et al. 2002]. Most of the actions of Ang II, including vasoconstriction, aldosterone stimulation, angiogenesis stimulation and cell growth are mediated by the Ang II type 1 (AT1) receptor. Only recently the Ang II type 2 (AT2) receptor was described and is shown to be upregulated during fetal development, and implicated in the reduction in neointima formation after vascular injury, reduction in endothelial cell growth and migration, and vasodilation [Csikos et al. 1998; Arima et al. 1997; Janiak et al. 1992; Haberl et al. 1990]. Recently, a selective Ang-(1-7) receptor antagonist [D-alanine7-angiotensin-(1-7}] (D-Ala or A779) that does not interact with either the AT1 or AT2 receptor was characterized. Using this antagonist, a specific Ang-(1-7) (AT1-7) receptor was identified and a role for Ang-(1-7) in blood pressure regulation, vasodilation and electrolyte excretion has been shown [Abbas et al. 1997; Ardaillou, 1997; Lima et al. 1997; Erdos, 1996; Santos et al. 1996; Porsti et al. 1994; Botelho et al. 1993]. More recently Santos et al. [2003] showed that Ang-(1-7) binds with high affinity to the Mas-G protein coupled receptor. Previously shown Ang-(1-7) functions, including a vasodilator response and antidiuresis in water-loaded animals, were absent in Mas knockout mice.

Circulating and tissue-specific renin–angiotensin system in normal pregnancy and pre-eclampsia

In normal pregnancy, estrogen causes an overexpression of the RAS by increasing both tissue and circulating levels of angiotensinogen [Tewksbury, 1990; Nasjletti and Masson, 1972] and renin [Chen et al. 1992; Rubattu et al. 1991; Glorioso et al. 1986; Howard et al. 1988). During pregnancy, there is a large increase in plasma angiotensinogen due to stimulation of its hepatic synthesis by estrogen [Alhenc-Gelas et al. 1986; Oelkers, 1996]. In pre-eclampsia, plasma angiotensinogen is generally unchanged when compared to normotensive pregnancy [Brown et al. 1997]. In association with increased circulating estrogen, maternal prorenin and renin are also increased during pregnancy [Alhenc-Gelas et al. 1986]. Prorenin reaches a peak within 20 days after conception and remains high until parturition [August and Sealey, 1990; August et al. 1990]. Plasma renin activity rises during the first few weeks of pregnancy. Plasma renin activity and aldosterone levels are usually normal or lower in pre-eclamptic women. Plasma Ang II is increased in association with the rise of angiotensinogen and plasma renin activity during normal gestation [Baker et al. 1990; Brown et al. 1997]. In addition, increased urinary and plasma aldosterone levels are found during pregnancy [Brown et al. 1997; August and Sealey, 1990]. Pregnant women and animals are resistant to the pressor effects of Ang II [Baker et al. 1992; Gant et al. 1973; Chesley et al. 1965], and they remain normotensive despite a two-fold increase in Ang II. In addition, studies have demonstrated that plasma Ang II levels are normal or decreased in women with pre-eclampsia [Granger et al. 2001; Chesley, 1999). In pregnant animals, administration of ACE inhibitors results in a decrease in blood pressure, demonstrating the tonic role of Ang II in blood pressure maintenance during pregnancy [Ferris and Weir, 1983]. Our group has shown, in pre-eclamptic subjects, that serum ACE is increased when compared with normal pregnant subjects; however, there is no difference in non-pregnant subjects [Merrill et al. 2002]. Dr Ferrario and colleagues have demonstrated that Ang-(1-7) contributes to the blood pressure lowering effects of ACE inhibitors in experimental animals [Iyer et al. 1998]. Therefore, Ang-(1-7) is a potential factor that may be contributing to the normal blood pressure by balancing the vasoconstrictor actions of elevated Ang II. Previously Brosnihan et al. have demonstrated that estrogen shifts the pathways of formation of the angiotensin peptides in a tissue-specific manner, reducing the formation of Ang II and augmenting the production of Ang-(1-7) in Sprague Dawley (SD) and (mRen2) transgenic (Tg) rats [P. Li et al. 1997b]. The vasoactive actions of Ang-(1-7) oppose the Ang II effects [Brosnihan et al. 1996; Porsti et al. 1994; Peach and Levens, 1980; Bumpus and Smeby, 1962] by the release of vasodilator prostaglandins [Jaiswal et al. 1991a, 1991b, 1991c; Tallant et al. 1991a, 1991b] and nitric oxide (NO) [P. Li et al. 1997a; Osei et al. 1993]. Local vasodilator actions of Ang-(1-7) in mesenteric and hindlimb regions were shown to be mediated by NO [Osei et al. 1993). Our lab recently showed that pregnancy augments the vasodilatory actions of Ang-(1-7) in isolated mesenteric vessels [Neves et al. 2003]. We also showed that human urinary and plasma levels of Ang-(1-7) are increased in normal pregnant subjects [Merrill et al. 2002; Valdes et al. 2001]. In addition to the other components of the RAS including plasma angiotensinogen, renin activity, Ang I and Ang II, plasma Ang-(1-7) is increased during normal pregnancy. However, in pre-eclampsia, as with the other RAS components, Ang-(1-7) is reduced to a level similar to that of non-pregnant women [Merrill et al. 2002]. This study indicated that the circulating RAS is significantly upregulated in normal pregnant women and downregulatcd in women with pre-eclampsia. Levels of urinary Ang-(1-7) increase as pregnancy progresses reaching a peak at 35 weeks and decreasing immediately following birth or during the lactation period. Urinary Ang-(1-7) levels during pregnancy are 16- to 20-fold higher than non-pregnant subjects during the menstrual cycle [Valdes et al, 2001]. In pregnant rats, we demonstrated that Ang-(1-7) is increased in the kidney, uterus and urine; these findings indicated that pregnancy is a condition of over-expression of Ang-(1-7) [Brosnihan et al. 2004].

Uteroplacental renin–angiotensin system in normal and pre-eclamptic pregnancies

The components of the RAS are widely distributed throughout the uteroplacental unit. Angiotensinogen, renin, ACE, Ang I, Ang II, and the AT1 and AT2 receptors are found in the placenta, uterus (endometrium and myometrium), fetal membranes, and amniotic fluid [Hagemann et al. 1994]. Angiotensinogen mRXA has been previously shown to be present in the whole placenta throughout normal pregnancy starting at 6 weeks of gestation [Cooper et al. 1998; Paul et al. 1993] and in uterine decidual spiral arteries in the first and second trimester of normal pregnancy [Morgan et al. 1997). Renin gene expression in the placenta of normal and pre-eclamptic pregnancies was found in a study by Shah et al. [2000] where the placenta was microdissected into chorionic villous tissue, decidua basalis and decidua vera. In addition, measurements of total renin concentration and active renin were shown to be significantly higher in pre-eclamptic placentas [Singh et al. 2004], Ang II expression has been seen in the placenta, chorion and amnion of full-term normal and pre-eclamptic women [Kalenga et al. 1996]. In addition, Ang II expression has been observed in the non-pregnant human uterus [X.-F. Li and Ahmed, 1997b, 1996]; however, its levels seem to undergo cyclic changes in the endometrium. During the proliferative phase, Ang II immunoreactivity was seen in the glandular epithelium and stroma, while in the secretory phase, immunoreactivity was observed in the perivascular stromal cells around the endometrial spiral arterioles (Ahmed et al. 1995]. The human placenta and uterus contain high levels of ACE. In the human placenta, ACE activity increased during the course of pregnancy, whereas ACE mRNA expression increased initially and then decreased near term [Yagami et al. 1994]. ACE expression has been shown in previous studies using quantitative reverse transcriptase (RT), real-time PCR and radioenzymatic assay in normal and pre-eclamptic whole placentas and in chorionic villous tissue alone [Herse et al. 2007; Ito et al. 2002; Kalenga et al. 1996]. ACE immunoreactivity in the human uterus again showed cyclic variation in the endometrium similar to that seen with Ang II. The highest expression of ACE was observed in the late secretory phase and during menses [X.-F. Li et al. 1997a].

Not many studies have been done to assess the expression of Ang-(1-7) and its processing enzyme, ACE2, in the uteroplacental unit in humans; however, recently we demonstrated by immunohistochemistry that Ang-(1-7) is widely distributed throughout the human and rat fetal placental unit during gestation [Neves et al. 2007; Valdes et al. 2006]. In both the human and rat, Ang-(1-7) immunoreactivity was colocalized with ACE2. Immunocytochemical expression of Ang-(1-7) and ACE2 was found in human placental syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi, and invading and intravascular trophoblast (Figure 1).

Fig. 1Fig. 1
Localization of Ang-[1-7) and ACE2 in the placenta. The diagram shows a cross-section of the human placenta illustrating the sections of the placenta and decidua that were stained for Ang-[1-7] and ACE2 by immunohistochemistry. In this diagram, different ...

In addition, Ang-(1-7) was increased in spontaneously aborted first trimester placentas suggesting that the elevated levels of Ang-(1-7) may be playing a role in abnormal development. In the umbilical cord from third trimester pre-eclamptic pregnancies, Ang-(1-7) and ACE2 were localized in the arterial and venous endothelium and smooth muscle. In addition, ACE2 was increased in the arterial endothelium. These findings suggest that the local expression of Ang-(1-7) and ACE2 may play a critical role in the placenta and may differ from the regulation of the circulating RAS. In addition, in the rat, intense staining was verified in the fetal membranes. Ang-(1-7) and ACE2 were also expressed in luminal and glandular epithelium of the uterine myometrium [Neves et al. 2007] which is expected since the RAS has been implicated in the process of implantation and decidualization [Hagemann et al. 1994].

Previous studies have shown that Ang II receptors of both type AT1 and AT2 are found in the placenta and fetal membranes of humans; however, the Ang II receptors in the human placenta are predominantly AT1 [X. Li et al. 1998; Knock et al. 1994], The AT1 receptors are localized in the cytotrophoblast and syncytiotrophoblasts in the placental villi, in extravillous trophoblast, and in and around the blood vessels of the placental villi. In the human placenta, both AT1 receptor mRNA and AT1 receptor protein increase from the first trimester onward reaching the highest levels at term [Petit et al. 1996]. In contrast, immunohistochemical studies have shown intense immunoreactivity for AT1 receptors in first and second trimester compared with term [Cooper et al. 1998]. A positive correlation between Ang II and the number of AT1 receptors were observed in the human placenta suggesting that Ang II regulates AT1 receptor expression [Kalenga et al. 1991].

Previous studies have shown an upregulation of mRNA expression of the AT1 receptor in the human pre-eclamptic placenta. In addition, the same study showed an increase in AT1 receptor protein in the pre-eclamptic placenta [Leung et al. 2001]. This indicates that the upregulation of the AT1 receptor in the placenta could play a pathophysiological role in patients with pre-eclampsia. However, there is some controversy surrounding the regulation of AT1 receptors during pre-eclampsia. It has been shown that the capacity and affinity of AT1 binding sites were significantly lower in placentas from pregnancies complicated by pre-eclampsia and intrauterine growth restriction compared to normal-term controls [X. Li et al. 1998; Knock et al. 1994].

In the uterus, the AT2 receptor has been shown to be the predominant Ang II receptor which is found mostly in the endometrium [Saridogan et al. 1996; Ahmed et al. 1995]. AT1 receptor expression is relatively low in the uterus and shows cyclic changes. During the proliferative phase, AT1 expression is found in the glandular epithelium and stroma [Ahmed et al. 1995] while in the secretory phase the AT1 expression is mostly in the perivascular stromal cells around the endometrial spiral arterioles [Ahmed et al. 1995]. In the non-pregnant uterus, specifically in the myometrium, the Ang II receptors are almost exclusively AT2 receptors [Cox et al. 1996; Saridogan et al, 1996]. During pregnancy, AT2 receptor mRNA and protein are downregulated [Matsumoto et al. 1996; de Gasparo et al. 1994]. The human rnyometrium contains low levels of the AT1 receptor in the non-pregnant state. No downregulation of the AT1 receptor expression has been observed in the uterus during pregnancy, therefore the regulation of the AT1 receptor seems to be different from the AT2 receptor [Cox et al. 1996; Matsumoto et al. 1996; de Gasparo et al. 1994]. Evidence for the presence of a non-AT1/non-AT2 receptor was found in the human placenta [X. Li et al. 1998] and has been speculated to be an AT 1-7 receptor. This receptor has been linked with the biological actions of Ang-(1-7) [Ferrario et al. 1998].

In order to help clarify the discrepancies seen in the previous literature and to more thoroughly investigate the chorionic villi, an essential part of the placenta responsible for regulating nutrient and oxygen exchange between the mother and fetus, we recently completed a comprehensive examination of the RAS in the human chorionic villi of normal and pre-eclamptic pregnancies [Anton et al. 2008]. In this study, we collected placenta tissues from third trimester, nulliparous normal (n = 25) and pre-eclamptic (n = 21) subjects for measurement of angiotensin peptides, Ang I, Ang II and Ang-(1-7), by radioimmunoassay or for angiotensinogen (Aogen), renin, ACE, ACE2, NEP, and AT1, AT2 and Mas receptor mRNA by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In addition, chorionic villi were analyzed by receptor autoradiography to determine the maximal density and percentage of each receptor subtype, AT1, AT2 and AT1-7. In this study we found that Ang II levels in the chorionic villi were significantly higher in pre-eclamptic subjects when compared with normal pregnant women. However, there were no differences in either Ang I or Ang-(1-7) peptide levels (Figure 2). In addition to elevated Ang II peptide levels, Aogen and AT1 receptor mRNAs were significantly increased in pre-eclamptic chorionic villi (Figure 3). No differences were seen in renin (Figure 3), ACE, ACE2 or NEP mRNA in normal pregnant versus pre-eclamptic chorionic villi. Interestingly, Mas receptor mRNA concentrations were significantly decreased in the chorionic villi from pre-eclamptic women (Figure 3). AT2 receptor mRNA was found to not be detectable in either normal or pre-eclamptic chorionic villi. Receptor autoradiography experiments showed that the AT1 receptor subtype is the predominant angiotensin receptor in chorionic villi of both normal and pre-eclamptic women (Figure 4). However, there was no difference in AT1 receptor density between normal and pre-eclamptic chorionic villi (Table 1). In addition, the AT2 and AT1-7 receptor subtypes were not different between normal and pre-eclamptic subjects but made up less than 15% of the total RAS receptors in the chorionic villi. This study indicates that elevated Ang II, acting through the AT1 receptor, could be contributing to the vasoconstriction of the fetal vessels found within the chorionic villi. This finding could be responsible for impaired placement-fetal blood flow and a decrease in fetal nutrition and oxygenation observed during pre-eclampsia.

Fig. 2
Angiotensin peptide expression in the chorionic villi of normal and pre-eclamptic pregnancies. Measurement of the RAS peptides Ang I [A], Ang II [B], and Ang-[1-7] [C] by radioimmunoassay revealed an increase in Ang II expression in pre-eclamptic chorionic ...
Fig. 3
Relative gene expression of angiotensinogen, renin, AT1 receptor, and Mas receptor in the chorionic villi of normal and pre-eclamptic pregnancies. Angiotensinogen [A], renin [B], AT1 receptor [C], and Mas receptor [D] mRNAs were measured by real time ...
Fig. 4
Receptor binding of angiotensin receptor subtypes in the chorionic villi of normal and pre-eclamptic pregnancies. Receptor binding of RAS receptor subtypes. AT1, AT2, and AT1-7, was measured by receptor autoradiography utilizing radiolabeled 125I-Sarthran. ...
Table 1
Quantification of receptor density of RAS receptor subtypes in normal and pre-eclamptic chorionic villi.

AT1 receptor autoantibodies in pre-eclampsia

Recent studies have observed the presence of an IgG autoantibody in the serum of pre-eclamptic women that stimulates the AT1 receptor [Wallukat et al. 1999]. These antibodies are referred to as AT1 autoantibodies (AT1-AA). In this study, using a bioassay consisting of spontaneously beating neonatal rat cardiomyocytes, the authors showed that AT1-AA increased the beating rate of these cardiomyocytes. In addition, it was shown that the increased beating rate could be blocked by treatment with the AT1 receptor antagonist, losartan, but nor the AT2 receptor antagonist, PD123319 (PD). The AT1-AA has been shown to bind to the second extracellular loop of the AT1 receptor [Wallukat et al. 1999] and act as an agonist at the AT1 receptor. In this same study, it was also discovered that the bioassay cardiac contraction rate was decreased by 50% 1 week after delivery suggesting that these autoantibodies rapidly decrease following birth. It has been further shown that AT1-AA bind directly to the AT1 receptor in vascular smooth muscle cells (VSMC) through colocalization and coimmunoprecipitation studies [Dechend et al. 2000].

The role of AT1-AA in pre-eclampsia is unclear; however, several studies have shown that many features of pre-eclampsia could be explained by the ability of AT1-AA to stimulate the AT1 receptor. AT1-AA have been shown to stimulate tissue factor (TF) production and plasminogen activator inhibitor (PAI-1) initiating hypercoagulation and reducing fibrinolytic activity in pre-eclamptic women [Walther et al. 2005; Dechend et al. 2000]. AT1-AA induce reactive oxygen species generation, mediated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, in VSMCs and trophoblasts which could contribute to the inflammatory responses associated with pre-eclampsia [Dechend et al. 2003]. AT1-AA are found in pregnant women who have impaired placental development and abnormal uterine perfusion as shown by Doppler ultrasound and are absent in women with normal Doppler ultrasound indicating that AT1-AA track with abnormal placental development and may be used as an early marker to identify women at risk for intrauterine growth restriction (IUGR) or pre-eclampsia [Walther et al. 2005], In a more recent study, it has been suggested that AT1-AA functioning as Ang II agonists from pre-eclamptic women induce soluble vascular endothelial growth factor receptor-1 (sVEGFR1 or sFlt1), an antiangiogenic receptor produced in the placenta, by angiotensin receptor activation and downstream calcineurin/nuclear factor of activated T (NFAT) cell signaling [Zhou et al. 2008]. Although the cause of pre-eclampsia remains unknown, these studies have shown that AT1-AA activate AT1 receptors to produce several biological responses seen in women with pre-eclampsia indicating that AT1-AA play a critical role in understanding the possible mechanisms leading to the development of this disease.


Despite extensive research, the pathological cause of pre-eclampsia remains unknown. Pre-eclampsia is a complex disease that has been shown in previous studies to involve many different biochemical and pathophysiological pathways leading to the thought that the development of pre-eclampsia is the result of many intersecting cellular and molecular factors. The studies described in this review provide evidence that both the circulating and uteroplacental RAS play an important role in understanding the mechanisms responsible for the development of pre-eclampsia. In addition, the differential regulation that exists between the circulating and uteroplacental RAS (Figure 5) indicates that abnormal regulation of the RAS seen in women with pre-eclampsia might originate in placental tissues, including the cells of the chorionic villi, which are essential for maternal–fetal nutrient and oxygen exchange. However, more studies are warranted in order to understand the mechanisms responsible for the change in RAS regulation during pre-eclampsia. In addition the molecular downstream regulation of RAS components, including Ang II and Ang-(1-7), in normal pregnancy and pre-eclampsia should be investigated more thoroughly in order to completely understand the impact of the RAS in the development of pre-eclampsia.

Fig. 5
Contrasting changes in the Ang II levels found in the circulation and chorionic villi of normal and pre-eclamptic pregnancy. Expression of Ang II is significantly decreased in the circulation of pre-eclamptic women. However, the expression of local tissue ...


The authors gratefully acknowledge Elizabeth Erickson for her artistic rendering of the diagram of the placenta seen in Figure 1. This work was supported in part by grants from the National Institutes of Health, NHLBI-P01 HL51952 and HL67363. L. Anton was supported in part by a pre-doctoral grant awarded by the Mid-Atlantic American Heart Association (AHA0515221U). The authors gratefully acknowledge grant support in part provided by Unifi, In. Greensboro, NC and Farley-Hudson Foundation, Jacksonville, NC.

Contributor Information

Lauren Anton, Hypertension and Vascular, Research Center, Wake, Forest University School, of Medicine, Winston-Salem, North Carolina, USA.

K. Bridget Brosnihan, Hypertension and Vascular, Research Center, Wake, Forest University School, of Medicine, Winston-Salem, North Carolina, USA, ude.cmbufw@hinsorbb.


  • Abbas A, Gorelik G, Carbini LA, Scicli AG. Angiotensin-(1-7) induces bradykinin-mediated hypotensive responses in anesthetized rats. Hypertension. 1997;30:217–221. [PubMed]
  • Ahmed A, Li XF, Shams M, Gregory J, Rollason T, Barnes NM. Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site. J Clin Invest. 1995;96:848–857. [PMC free article] [PubMed]
  • Alhenc-Gelas R, Tache A, Saint-Andre JP, Milliez J, Sureau C, Corvol P, et al. The Renin–Angiotensin System in Pregnancy and Parturition. Adv Nephrol Necker Hoap. 1986;15:25–33. [PubMed]
  • Allred AJ, Diz DI, Ferrarrio CM, Chappell MC. Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues. Am J Physiol. 2000;279:F841–F850. [PubMed]
  • Anton L, Merrill DC, Neves LAA, Stovall K, Gallagher PE, Diz DI, et al. Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia. Hypertension. 2008;51:1066–1072. [PMC free article] [PubMed]
  • Ardaillou R. Active fragments of angiotensin II: enzymatic pathways of synthesis and biological effects. Curr Opin Nephrol Hypertens. 1997;6:28–34. [PubMed]
  • Arima S, Endo Y, Yaoita H, Omata K, Ogawa S, Tsunoda K, et al. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechansim of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J Clin Invest. 1997;100:2816–2323. [PMC free article] [PubMed]
  • August P, Lenz T, Ales KL, Druzin ML, Edersheim TG, Hutson JM, et al. Longitudinal study of the renin–angiotensin–aldosterone system in hypertensive pregnant women: Deviations related to the development of superimposed preeclampsia. Am J Obstetr Gynecol. 1990;163:1612–1621. [PubMed]
  • August P, Seaky JB. Renin–Angiotensin System in Normal and Hypertensive Pregnancy and in Ovarian Function. In: Laragh JH, Brenner BM, editors. Hypertension pathophysiology, diagnosis, and management. New York: The Raven Press; 1990. pp. 1761–1778.
  • Baker PN, Pipkin FB, Symonds EM. Platelet angiotensin II binding and plasma renin concentration, plasma renin substrate and plasma angiotensin II in human pregnancy. Clin Sci. 1990;79:403–408. [PubMed]
  • Baker PN, Pipkin FB, Symonds EM. Comparative study of platelet angiotensin II binding and the angiotensin II sensitivity test as predictors of pregnancy-induced hypertension. Clin Sci. 1992;83:89–95. [PubMed]
  • Botelho LMO, Neves LA, Block CH, Khosla MC, Santos RAS. Evidence that angiotensin-(l-7) is an osmoregulatory peptide: Increased plasma levels in dehydration and hemorrhage. Hypertension. 1993;21:603.
  • Bravo EL, Tarazi RC, Dustan HP. Multifactorial analysis of chronic hypertension induced by electrolyte-active steroids in trained unanesthetized dogs. Circ Res. 1977;40(Suppl I):140–145. [PubMed]
  • Bricca G. Alternative production pathways of angiotensins and differential cardiovascular remodelling. J Hypertens. 2002;20:1943–1944. [PubMed]
  • Brosnihan KB, Li P, Ferrario CM, et al. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27:523–528. [PubMed]
  • Brosnihan KB, Neves LA, Anton L, Joyner J, Valdes G, Merrill DC. Enhanced expression of Ang-(l-7) during pregnancy. Braz J Med Biol Res. 2004;37:1255–1262. [PubMed]
  • Brosnihan KB, Neves LA, Joyner J, Averill DB, Chappell MC, Sarao R, et al. Enhanced renal immunocytochemical expression of ANG-(l-7) and ACE2 during pregnancy. Hypertension. 2003;42:749–753. [PubMed]
  • Brosnihan KB, Santos RAS, Block CH, Schiavone MT, Welches WR, Chappell MC, et al. Biotransformation of angiotensins in the central nervous system. Ther Res. 1988;9:48–59.
  • Brown MA, Wang J, Whotworth JA. The renin–angiotensin–aldosterone system in pre-eclampsia. Clin Exp Hypertens. 1997;19:713–726. [PubMed]
  • Bumpus EM, Smeby RR. Importance of amino acid side groups for biologic activity of angiotensin II. Circulation. 1962;25:183–185. [PubMed]
  • Chen Y, Naftilan AJ, Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension. 1992;19:456–463. [PubMed]
  • Chesley LC. Renal and cardiovascular alterations. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley’s hypertension disorders in pregnancy. Stamford, CT: Appleton & Lange; 1999. pp. 263–326.
  • Chesley LC, Talledo E, Bohler CS, Zuspan FP, et al. Vascular reactivity to angiotensin II and norepinephrine in pregnant and nonpregnant women. Am J Obstetr Gynecol. 1965;91:837–842. [PubMed]
  • Cooper AC, Robinson G, Vinson GP, Cheung WT, Broughton-Pipkin F. The localization and expression of the renin–angiotensin system in the human placenta throughout pregnancy. Placenta. 1998;20:467–474. [PubMed]
  • Cox BE, Word RA, Rosenfield CR. Angiotensin II receptor characteristics and subtype expression in uterine arteries and myometrium during pregnancy. J Clin Endocrinol Metab. 1996;81:49–58. [PubMed]
  • Crackower MA, Sarao R, Oudit GY, Yagil C, Kozierdazki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–828. [PubMed]
  • Csikos T, Chung O, Unger T. Receptors and their classification: focus on angiotensin II and the AT2 receptor. J Human Hypertens. 1998;12:311–318. [PubMed]
  • Damsky CH, Fitzgerald ML, Fisher SJ. Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest. 1992;89:210–222. [PMC free article] [PubMed]
  • de Gasparo M, Whitebread S, Kalanga MK, De Hertogh R, Crevoisier P, Thomas K. Down regulation of the angiotensin II receptor subtype AT2 in human myometrium during pregnancy. Regul Pept. 1994;53:39–45. [PubMed]
  • Dechend R, Homuth V, Wallukat G, Kreuzer J, Park JK, Theuer J, et al. AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor [see comments] Circulation. 2000;101:2382–2387. [PubMed]
  • Dechend R, Viedt C, Muller DN, Ugele B, Brandes RP, Wallukat G, et al. AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation. 2003;107:1632–1639. [PubMed]
  • Erdos EG. News about ACE, or, the separate lives of ‘Siamese twin’ domains. J Clin Invest. 1996;97:588. [PMC free article] [PubMed]
  • Ferrario CM, Chappell MC. A new myocardial conversion of angiotensin I. Curr Opin Cardiol. 1994;9:520–526. [PubMed]
  • Ferrario CM, Chappell MC, Dean RH, Iyer SN. Novel angiotensin peptides regulate blood pressure, endothelial function and natriuresis. J Am Soc Nephrol. 1998;9:1716–1722. [PubMed]
  • Ferris TF, Weir EK. Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest. 1983;71:809–815. [PMC free article] [PubMed]
  • Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest. 1973;52:2682–2689. [PMC free article] [PubMed]
  • Genest J, Nowaczynski W, Kuchel O, Boucher R, Rojo-Ortega JM. The role of the adrenal cortex in human essential hypertension. Mayo Clin Proc. 1977;52:291–307. [PubMed]
  • Glorioso N, Altas SA, Laragh JH, Jewelewicz R, Sealey JE. Prorenin in high concern rations in human ovarian follicular fluid. Science. 1986;233:1422–1424. [PubMed]
  • Gordon RD, Klemm SA, Tunny TJ, Stowasser M. Primary aldosteronism: Hypertension with a genetic basis. Lancet. 1992;340:159–161. [PubMed]
  • Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens. 2001;14:178S–185S. [PubMed]
  • Haberl RL, Anneser F, Villringer A, Einhaupl KM. Angiotensin II induces endothelium-dependent vasodilation of rat cerebral arterioles. Am J Physiol. 1090;258:H1840–H1846. [PubMed]
  • Hagemann A, Nielsen AH, Poulsen K. The uteroplacental renin–angiotensin system: a review. Exp Clin Endocrinol. 1994;102:252–261. [PubMed]
  • Hall JE, Brands MW. The Renin–Angiotensin–Aldosterone Systems – Renal Mechanisms and Circulatory Homeostasis. In: Seldin DW, Giebisch G, editors. The renin–angiotensin–aldosterone systems. New York: Raven Press; 1992. pp. 1455–1504.
  • Hall JE, Mizelle HL, Brands MW, Hildebrandt DA. Pressure natriuresis and angiotensin II in reduced kidney mass, salt-induced hypertension. Am J Physiol. 1992;262:R61–R71. [PubMed]
  • Herse E, Dechend R, Harsern NK, Wallukat G, Janke J, Qadri F, et al. Dysregulation of the circulating and tissue-based renin–angiotensin system in preeclampsia. Hypertension. 2007;49:604–611. [PubMed]
  • Howard RB, Hosokawa T, Maguire MH. Rat ovarian renin: Characterization and changes during the estrous cycle. Endocrinology. 1988;123:2331–2340. [PubMed]
  • Ito M, Itakura A, Ohno Y, Nomura M, Senga T, Nagasaka T, et al. Possible activation of the renin–angiotensin system in the feto-placental unit in preeclampsia. J Clin Endocrinol Metab. 2002;87:1871–1878. [PubMed]
  • Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1–7) contributes to the antihypertensive effects of blockade of the renin–angiotensin system. Hypertension. 1998;31:356–361. [PubMed]
  • Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells. Am J Physiol. 1991a;260:RS1000–R1006. [PubMed]
  • Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. The non-peptide angiotensin II antagonist DuP 753 is a potent stimulus for prostacyclin synthesis. Am J Hypertens. 1991b;4:228–233. [PubMed]
  • Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes. Hypertension. 1991c;17:1115–1120. [PubMed]
  • Janiak P, Pillon A, Prost JF, Vilaine JP. Role of angiotensin subtype 2 receptor in neointima of rat aorta. Hypertension. 1992;20:737–745. [PubMed]
  • Kalenga MK, De Hertogh R, Whitebread S, Vankrieken L, Thomas K, de Gasparo M. Distribution of the concentrations of angiotensin II (A II), A II receptors, hPL, prolactin, and steroids in human fetal membranes. Rev Fr Gynecol Obstet. 1991;86:585–591. [PubMed]
  • Kalenga MK, Thomas K, de Gasparo M, De Hertogh R. Determination of renin, angiotensin converting enzyme and angiotensin II levels in human placenta, chorion and amnion from women with pregnancy induced hypertension. Clin Endocrinol. 1996;44:429–433. [PubMed]
  • Knock GA, Sullivan MH, McCarthy A, Elder MG, Polak JM, Wharton J. Angiotensin II (AT1) vascular binding sites in human placentae from normal-term, preeclamptic and growth retarded pregnancies. J Pharmacol Exp Ther. 1994;271:1007–1015. [PubMed]
  • Laragh JH. The rertin system and four lines of hypertension research: nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack. Hypertension. 1992;20:267–279. [PubMed]
  • Leung PS, Tsai SJ, Wallukat G, Leung TN, Lau TK. The upregulation of angiotensin II receptor AT(1) in human preeclamptic placenta. Mol Cell Endocrinol. 2001;184:95–102. [PubMed]
  • Li P, Chappell MC, Ferrario CM, Brosnihan KB. Angiotensin-(1–7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension. 1997a;29:394–400. [PubMed]
  • Li P, Ferrario CM, Ganten D, Brosnihan KB. Chronic estrogen treatment in female transgenic (mRen2)27 hypertensive rats augments endothelium-derived nitric oxide release. Am J Hypertens. 1997b;10:662–670. [PubMed]
  • Li X, Shams M, Zhu J, Khalig A, Wilkes M, Whittle M, et al. Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants. J Clin Invest. 1998;101:442–454. [PMC free article] [PubMed]
  • Li XF, Ahmed A. Dual role of angiotensin II in the human endometrium. Human Reproduction. 1996;11:95–108. [PubMed]
  • Li XF, Ahmed A. Compartmentalization and cyclic variation of immunoreactivity of renin and angiotensin converting enzyme in human endometrium throughout the menstrual cycle. Hum Reprod. 1997a;12:2804–2809. [PubMed]
  • Li XF, Ahmed A. Expression of angiotensin II and its receptor subtypes in endometrial hyperplasia: A possible role in dysfunctional menstruation. Lab Invest. 1997b;75:137–145. [PubMed]
  • Lima CV, Paula RD, Rsende FL, Khosla MC, Santos RAS. Potentiation of the hypotensive effect of bradykinin by short-term infusion of angiotensin-(1–7) in normotensive and hypertensive rats. Hypertension. 1997;30:542–548. [PubMed]
  • MacGregor GA, Markandu ND, Roulston JE, Jones JC, Morton JJ. Maintenance of blood pressure by the renin–angiotensin system in normal man. Nature. 1981;291:329–331. [PubMed]
  • Matsumoto T, Sagawa N, Mukoyama M, Tanaka I, Itoh H, Goto M, et al. Type 2 angiotensin II receptor is expressed in human myometrium and uterine leiomyoma and is down-regulated during pregnancy. J Clin Endocrinol Metab. 1996;81:4366–4372. [PubMed]
  • Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB. Angiotensin-(1–7) in normal and preeclamptic pregnancy. Endocrine. 2002;18:239–245. [PubMed]
  • Moldenhauer JS, Sibai BM. Hypertensive Disorders of Pregnancy. In: Scott JR, Gibbs RS, Karlan BY, Haney AF, editors. Danforth’s obsterics and gynecology. Lippincort Williams and Wilkins; Baltimore, MD: 2003. pp. 257–272.
  • Morgan T, Craven C, Nelson L, Lalouel JM, Ward K. Angiotensinogen T235 expression is elevated in decidual spiral arteries. J Clin Invest. 1997;100:1406–1415. [PMC free article] [PubMed]
  • Nasjletti A, Masson GMG. Studies on angiotensinogen formation in a liver perfusion system. Circ Res. 1972;30(Suppl II):187–202. [PubMed]
  • Neves LAA, Williams AF, Averill DB, Ferrario CM, Walkup MP, Brosnihan KB. Pregnancy enhances the angiotensin (Ang)-(1–7) vasodilator response in mesenteric arteries and increases the renal concentration and urinary excretion of Ang-(1–7) Endocrinology. 2003;14:3338–3343. [PubMed]
  • Neves LAA, Stovall K, Joyner J, Valdes G, Gallagher PE, Ferrario CM, et al. ACE2 and Ang-(1–7) in the uterus during early and late gestation. Am J Physiol Regul Integr Comp Physiol. 2007;294:R151–161. [PubMed]
  • Oelkers WKH. Effects of estrogens and pro-gestogens on the renin-aldosterone system and blood pressure. Steroids. 1996;61:166–171. [PubMed]
  • Osei SY, Ahima RS, Minkes RK, Weaver JP, Khosla MC, Kaduwitz PJ. Differential responses to angiotensin-(1–7) in the feline mesenteric and hindquarters vascular beds. Eur J Pharmacol. 1993;234:35–42. [PubMed]
  • Paul M, Wagner J, Dzau VJ. Gene expression of the renin–angiotensin system in human tissues. J Clin Invest. 1993;91:2058–2064. [PMC free article] [PubMed]
  • Peach MJ, Levens NR. Molecular Approaches to the Study of Angiotensin Receptors. Proc of 14th midwest conference on Endocrinology and metabolism; New York: Plenum Press; 1980. pp. 191–194.
  • Petit A, Geoffroy P, Belisle S. Expression of angiotensin II type-I receptor and phospholipase C-linked G alpha q/11 protein in the human placenta. J Soc Gynecol Investig. 1996;3:316–321. [PubMed]
  • Porsti I, Bara AT, Busse R, Hecker M. Release of nitric oxide by angiotensin-(1–7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol. 1994;111:652–654. [PMC free article] [PubMed]
  • Rubattu S, Quimby FW, Sealey JE. Tissue renin and prorenin increase in female cats during the reproductive cycle without commensurate changes in plasma, amniotic or ovarian follicular fluid. J Hypertens. 1991;9:525–535. [PubMed]
  • Santos RAS, Semoes e Silva AC, Marie C, Silva DM, Machado RP, de Bul I, et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 2003;100:8258–8263. [PMC free article] [PubMed]
  • Santos RAS, Silva ACS, Magaldi AJ, Khosla MC, Ceasr KR, Passaglio KT, et al. Evidence for a physiological role of angiotensin-(1–7) in the control of hydroelectrolyte balance. Hypertension. 1996;27:875–884. [PubMed]
  • Saridogan E, Djahanbakhch O, Puddefoot JR, Demotroulis C, Dawda R, Hall AJ, et al. Type 1 angiotensin II receptors in human endometrium. Mol Hum Reprod. 1996;2:659–664. [PubMed]
  • Shah DM, Banu JM, Chirgwin JM, Tekmal RR. Reproductive tissue renin gene expression in preeclampsia. Hypertension In Pregnancy. 2000;19:341–351. [PubMed]
  • Singh HJ, Rahman A, Larmie ET, Nila A. Raised prorenin and renin concentrations in pre-eclamptic placentae when measured after acid activation. Placenta. 2004;25:631–636. [PubMed]
  • Tallant EA, Diz DI, Khosla MC, Ferrario M. Identification and regulation of angiotensin II receptor subtypes on NG108-15 cells. Hypertension. 1991a;17:1135–1143. [PubMed]
  • Tallant EA, Jaiswal N, Diz DI, Ferrario CM, et al. Human astrocytes contain two distinct angiotensin receptor subtypes. Hypertension. 1991b;18:32–39. [PubMed]
  • Tewksbury DA. Angiotensinogen -Biochemistry and Molecular Biology. In: Laragh JH, Brenner BM, editors. Hypertension:pathophysiology, diagnosis and management. New York: Raven Press; 1990. pp. 1197–1216.
  • Valdes G, Germain AM, Corthom J, Berrios C, Foradori AC, Ferrario CM, et al. Urinary vasodilator and vasoconstrictor angiotensins during menstrual cycle, pregnancy, and lactation. Endocrine. 2001;16:117–122. [PubMed]
  • Valdes G, Neves LAA, Anton L, Corthorn J, Chacon C, Germain AM, et al. Distribution of angiotensin-(1–7) and ACE2 in human placentas of normal and pathological pregnancies. Placenta. 2006;27:200–207. [PubMed]
  • Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme- related carboxypeptidase. J Biol Chem. 2002;277:14838–14843. [PubMed]
  • Vicovac L, Jones CJ, Aplin JD. Trophoblast differentiation during formation of anchoring villi in a model of the early human placenta in vitro. Placenta. 1995;16:41–56. [PubMed]
  • Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jupner A, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999;103:945–952. [PMC free article] [PubMed]
  • Walther T, Wallukat G, Jank A, Bartel S, Schultheiss HP, Faber R, et al. Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature. Hypertension. 2005;46:1275–1279. [PubMed]
  • Welches WR, Brosnihan KB, Ferrario CM. A comparison of the properties, and enzymatic activity of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. Life Sci. 1993;52:1461–1480. [PubMed]
  • Working Group on High Blood Pressure in Pregnancy. National High Blood Pressure Education Program (NHPEP) US Dept Health Human Service; 1991. Working Group Report on High Blood Pressure in Pregnancy; pp. 91-3029pp. 1–46.
  • Yagami H, Kurauchi O, Murata Y, Okamoto T, Mizutani S, Tomoda Y. Expression of angiotensin-converting enzyme in human placenta and its physiologic role in the fetal circulation. Obstet Gynecol. 1994;84:453–457. [PubMed]
  • Zhou C, Ahmad S, Mi T, Abbasi S, Xia L, Day MC, et al. Autoantibody from women with preeclampsia induces soluble fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated t-cells signaling. Hypertension. 2008;51:1010–9. [PMC free article] [PubMed]
  • Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest. 1997a;99:2152–2164. [PMC free article] [PubMed]
  • Zhou Y, Fisher SJ, Janatpour M, Genbacey O, Dejana E, Wheelock M, et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest. 1997b;99:2139–2151. [PMC free article] [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...