Longitudinal study of angiotensin peptides in normal and pre-eclamptic pregnancy.

PURPOSE: To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women. METHODS: Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation. Control samples were obtained at 6 weeks postpartum (PP). RESULTS: Mean blood pressure (p < 0.001) was elevated at 31-37 weeks of gestation in PE subjects as compared with NP subjects. Plasma Ang I and Ang II levels were elevated in NP subjects as early as 16 weeks of gestation and maintained throughout gestation. In PE subjects both plasma Ang I and Ang II were elevated at 16-33 weeks as compared with PP levels. PE subjects showed reduced plasma Ang I and Ang II (at 35-37 weeks of gestation) compared with NP subjects. Plasma Ang-(1-7) was unchanged in both groups. All three urinary peptides increased throughout gestation in NP subjects. In PE subjects urinary Ang I was increased at 23-26 weeks and was maintained throughout gestation. Urinary Ang II was increased at 27-29 and 31-33 weeks of gestation. PE subjects had no change in urinary Ang-(1-7). CONCLUSION: The activation of the RAS, particularly Ang II throughout normal gestation may contribute to the maintenance of vascular tone during normal pregnancy. However higher sensitivity to Ang II in pre-eclampsia may be potentiated by the higher circulating and urinary levels of Ang II, unopposed by local renal Ang-(1-7), and thus may contribute to the development of pre-eclampsia.

Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study.

BACKGROUND: During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy. METHODS: We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA. RESULTS: The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally. CONCLUSIONS: Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.

The uterine placental bed Renin-Angiotensin system in normal and preeclamptic pregnancy.

Previously, we demonstrated activation of the renin-angiotensin system in the fetal placental chorionic villi, but it is unknown whether the immediately adjacent area of the maternal uterine placental bed is regulated similarly. This study measured angiotensin peptides, renin-angiotensin system component mRNAs, and receptor binding in the fundus from nonpregnant subjects (n = 19) and in the uterine placental bed from normal (n = 20) and preeclamptic (n = 14) subjects. In the uterine placental bed from normal pregnant women, angiotensin II peptide levels and angiotensinogen, angiotensin-converting enzyme, angiotensin receptor type 1 (AT(1)), AT(2), and Mas mRNA expression were lower as compared with the nonpregnant subjects. In preeclamptic uterine placental bed, angiotensin II peptide levels and renin and angiotensin-converting enzyme mRNA expression were significantly higher than normal pregnant subjects. The AT(2) receptor was the predominant receptor subtype in the nonpregnant fundus, whereas all angiotensin receptor binding was undetectable in normal and preeclamptic pregnant uterine placental bed compared with nonpregnant fundus. These findings suggest that the maternal uterine placental bed may play an endocrine role by producing angiotensin II, which acts in the adjacent placenta to vasoconstrict fetal chorionic villi vessels where we have shown previously that AT(1) receptors predominate. This would lead to decreased maternal-fetal oxygen exchange and fetal nutrition, a known characteristic of preeclampsia.

Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia.

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. Angiotensinogen and AT(1) receptor gene expression was significantly higher in preeclamptic subjects. No differences were observed in renin, ACE, ACE2, or neprilysin gene expression. Mas receptor mRNA in preeclamptic subjects was decreased. The AT(1) receptor was the predominant receptor subtype in normal and preeclamptic chorionic villi. There was no difference in the density of the AT(1,) angiotensin II type 2, and angiotensin (1-7) receptors. These results indicate that enhanced chorionic villous expression of angiotensin II may result from increased angiotensinogen. Elevated angiotensin II, acting through the AT(1) receptor, may favor vasoconstriction in placental chorionic villi and contribute to impaired fetal blood flow and decreased fetal nutrition observed during preeclampsia.