A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia

Abstract

The present study tested the hypothesis that angiotensin II plays a role in the regulation of placental vascular tone, which contributes to hypertension in preeclampsia. Functional and molecular assays were performed in large and micro placental and non-placental vessels from humans and animals. In human placental vessels, angiotensin II induced vasoconstrictions in 78.7% vessels in 155 tests, as referenced to KCl-induced contractions. In contrast, phenylephrine only produced contractions in 3.0% of 133 tests. In non-placental vessels, phenylephrine induced contractions in 76.0% of 67 tests, whereas angiotensin II failed to produce contractions in 75 tests. Similar results were obtained in animal placental and non-placental vessels. Compared with non-placental vessels, angiotensin II receptors and β-adrenoceptors were significantly increased in placental vessels. Compared to the vessels from normal pregnancy, angiotensin II-induced vasoconstrictions were significantly reduced in preeclamptic placentas, which was associated with a decrease in angiotensin II receptors. In addition, angiotensin II and angiotensin converting enzyme in the maternal-placenta circulation in preeclampsia were increased, whereas angiotensin I and angiotensin1-7 concentrations were unchanged. The study demonstrates a selective effect of angiotensin II in maintaining placental vessel tension, which may play an important role in development of hypertension in preeclampsia.

Keywords: Pathology Section; angiotensin II; placenta vascular; preeclampsia.

Figure 1. Angiotensin II and PE induced concentration-dependent vasoconstrictions in HPV, HUV, and HUA

A. and D., representative images of AII- and PE-mediated dose-dependent vasoconstrictions in HPV-A3 A. and HUV D.. B., C., E. and F., AII and PE induced vasoconstrictions in HPV-A1/A2 (N = 25, n = 79 for AII; N = 22, n = 71 for PE), HPV-A3 (N = 54, n = 76 for AII; N = 40, n = 62 for PE), HUV (N = 28, n = 75 for AII; N = 21, n = 67 for PE), and HUA (N = 20, n = 53 for AII; N = 23, n = 58 for PE). AII, angiotensin II; PE, phenylephrine; HPV, human placental vessels; HUV, human umbilical vein; HUA, human umbilical artery; HPV-A1/A2, first-, second-order branch of umbilical vessels in placenta (mainly the main stem villous arteries); HPV-A3, the branch of the main stem villous arteries (micro-vessels with diameter around 150 um). Error bars denote s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001. N, number of participants; n, number of rings.

Figure 2. Angiotensin II and PE induced concentration-dependent vasoconstrictions in placenta vessels from normal and preeclamptic pregnancies

A., representative images of AII- and PE-mediated dose-dependent vasoconstrictions in HPV from preeclamptic pregnancies. B., and C., AII and PE induced vasoconstrictions in HPV-A1/A2 (N = 24, n = 46 for AII; N = 28, n = 54 for PE) and HPV-A3 (N = 23, n = 32 for AII; N = 25, n = 38 for PE) from preeclampsia. D., representative images of AII-mediated dose-dependent vasoconstrictions in HPV from normal and preeclamptic pregnancies. E., and F., AII induced concentration-dependent vasoconstrictions in HPV-A1/A2 (N = 25, n = 79 for NP; N = 24, n = 46 for P) and HPV-A3 (N = 54, n = 76 for NP; N = 23, n = 32 for P). NP, normal pregnancy; P, preeclampsia. Error bars denote s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001. N, number of participants; n, number of rings.

Figure 3. Expressions of AII and PE receptors in placental and non-placental vessels

A., and B., mRNA and protein levels of both AT1R and AT2R in HPV (N = 21) and HUV (N = 18). C., mRNA levels of PE multifarious receptors including ADRA1A, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, and ADRB2 in HPV (N = 20) and HUV (N = 15). D., and E., mRNA and protein levels of both AT1R and AT2R in NP (N = 23) and P (N = 18) placental vessels. F., mRNA levels of PE multifarious receptors in NP and P placental vessels (N = 18/group). NP, normal pregnancy; P, preeclampsia. Error bars denote s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001. N, number of participants.

Figure 4. Levels of RAS components (including AI A. and B., AII C. and D., Ang1-7 E. and F., and ACE G. and H., as well as epinephrine E. I. and J.), and norepinephrine (NE) K. and L. in maternal blood M., umbilical cord blood F., and placenta from normal and preeclamptic pregnancies (N = 12/group)

RAS, renin angiotensin system; AI, angiotensin I; AII, angiotensin II; Ang1-7, angiotensin1-7; ACE, angiotensin converting enzyme. NP, normal pregnancy; P, preeclampsia. Error bars denote s.e.m. *P < 0.05; **P < 0.01. N, number of participants.