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Ther Adv Cardiovasc Dis. Author manuscript; available in PMC Oct 1, 2009.
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PMCID: PMC2692864
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Systemic and uteroplacental renin–angiotensin system in normal and pre-eclamptic pregnancies

Abstract

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 3.4.15.1) 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.

Conclusion

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 ...

Acknowledgments

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.

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