The Localization and Expression of the Renin–angiotensin System in the Human Placenta Throughout Pregnancy

Cooper, Anthonya; Robinson, Graham; Vinson, Gavin P.; Cheung, Wing‐Tai; Pipkin, F. Broughton

doi:10.1053/plac.1999.0404

Cited by 92 publications

(73 citation statements)

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“…31,32 Previous studies also show that angiotensinogen mRNA is present in the whole placenta throughout normal pregnancy starting at 6 weeks of gestation 23,33 and in decidual spiral arteries in the first and second trimesters of normal pregnancy. 34 Angiotensinogen mRNA was higher in the chorionic villi obtained from preeclamptic subjects in our study.…”

Section: Discussionmentioning

confidence: 92%

“…21 This study suggested that the RAS may play an important role within the chorionic villi, an essential component of the placenta that is responsible for maternal-fetal blood flow and, thus, the transport of oxygen and nutrients to the growing fetus. Several studies investigated the local tissue-specific RAS in the placenta [22][23][24] ; however, none have characterized the entire RAS in the chorionic villi specifically. In this study, we investigated angiotensin peptides, RAS component mRNAs, and angiotensin receptor binding in chorionic villi from normal and preeclamptic subjects.…”

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confidence: 99%

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Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

et al. 2008

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Abstract-The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport.Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT 1 ), angiotensin II type 2, Mas receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Key Words: preeclampsia Ⅲ renin angiotensin system Ⅲ pregnancy Ⅲ placenta Ⅲ angiotensin receptors Ⅲ Mas receptor Ⅲ angiotensin (1-7) P reeclampsia, a hypertensive disorder of pregnancy, is clinically defined as maternal hypertension, proteinuria, and generalized edema occurring after the 20th week of gestation. Preeclampsia is the second leading cause of maternal mortality in the United States, affecting 7% to 10% of all pregnancies and contributing significantly to stillbirths and neonatal morbidity and mortality. 1 Thus, the prevention of preeclampsia would have a significant impact on maternal and neonatal outcome. Nevertheless, the pathophysiology of preeclampsia remains poorly understood. Although preeclampsia is often considered a multisystem disorder, one of the postulated pathological features of this disease is an impaired maternal uterine spiral artery remodeling. In preeclampsia, there is a decrease of embryonic trophoblast cell invasion of the uterine spiral arteries, which, in turn, prevents the diameter of these arteries from expanding and consequently leads to a reduction of blood flow into the placenta. 2,3 Without the remodeling of the uterine vasculature, the placenta becomes hypoxic as gestation advances, resulting in an oxygen deficiency within the tissue. The hypoxic placenta can then release factors into the maternal circulation that result in generalized endothelial dysfunction, vascular inflammation, and proteinuria. [3][4][5] Although several factors, including soluble fms-like tyrosine kinase 1 6 and soluble endoglin, 7 were discovered recently to play a role in the pathogenesis of preeclampsia, there are still many unanswered questions in the development of this disease.The renin-angiotensin system (RAS) is an important regulator of blood pressure, sodium, and fluid homeostasis and has been shown previously to play a role in preeclampsia. In normal pregnancy, estrogen causes an overexpression of the RAS by increasing both tissue and circulating levels of angiotensinogen 8,9 and renin. 10 -13 Consequently, plasma angiotensin (Ang) II is increased in association with the rise of angiotensinogen and plasma renin activity during gestation. 14,15 Normal pregnant women are resistant to the pressor effects...

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

et al. 2008

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“…Gant et al 31 identified hypersensitivity to infused Ang II in preeclamptic patients, although the Ang sensitivity test in preeclampsia is not invariably positive. 32 Sowers et al 33 found elevated active tissue renin concentrations and increased renin mRNA expression in placentas from preeclamptic Figure 5. TF activity from VSMC extracts exposed to treatments (meanϮSD).…”

Section: Discussionmentioning

confidence: 99%

AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

et al. 2000

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Background-We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT 1 -AA) directed at the AT 1 receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT 1 -AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT 1 -AA cause vascular smooth muscle cells (VSMC) to express TF. Methods and Results-IgG from preeclamptic patients containing AT 1 -AA was purified with anti-human IgG columns.AT 1 -AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT 1 receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT 1 -AA specificity by coimmunoprecipitating the AT 1 receptor with AT 1 -AA but not with nonspecific IgG. Angiotensin (Ang) II and AT 1 -AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT 1 -AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect. Conclusions-We conclude that AT 1 -AA and Ang II both stimulate the AT 1 receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT 1 -AA on human cells that could contribute to the pathogenesis of preeclampsia.

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“…Insufficient growth and development of the villous tree reduces the gaseous and nutrient transfer capacity of the placenta and can lead to fetal growth restriction (FGR), while shallow EVT invasion and impaired remodelling of uterine spiral arteries predispose to pre-eclampsia and FGR. Angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system, is locally generated in the placenta (Hosokawa et al 1985, Cooper et al 1999 and decidua (Shaw et al 1989), suggesting actions in regulating placental development. Indeed, many of the well-known actions of Ang II, including regulation of vascular contractility, osmoregulation (Peach 1981), cellular proliferation (Dinh et al 2001), angiogenesis (Le Noble et al 1991) and apoptosis (Yamada et al 1996), are key processes for placental development and function.…”

Section: Introductionmentioning

confidence: 99%

“…AGTR1 expression has been demonstrated in villous placenta throughout gestation, localised to syncytiotrophoblast and cytotrophoblast, Hofbauer cells and peri-vascular cells (Li et al 1998, Cooper et al 1999, Williams et al 2010. A low degree of AGTR2-specific binding of radiolabelled Ang II in placental homogenates provided evidence for low expression of the receptor (Li et al 1998), but studies using conventional RT-PCR have failed to confirm this finding (Cooper et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development

Tower

Liu²,

Charlesworth

et al. 2010

Reproduction

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Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal-fetal interface and explore the effects on cytotrophoblast turnover. Low levels of AGTR2 mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal-fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs.Reproduction (2010) 140 931-942

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The Localization and Expression of the Renin–angiotensin System in the Human Placenta Throughout Pregnancy

Cited by 92 publications

References 40 publications

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development

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The Localization and Expression of the Renin–angiotensin System in the Human Placenta Throughout Pregnancy

Cited by 92 publications

References 40 publications

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development

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AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor