Dataset Information

Estrogen Receptor-? Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression.

ABSTRACT: The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-?-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ER? upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ER? protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ER? bound in the pregnant state. ER? protein levels were similar but higher ER? protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ER? to the AT2R promoter in the nonpregnant state and ER? to the AT2R promoter in pregnancy; however, only ER? recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ER? (not ER?) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ER? (not ER?) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ER? in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.

SUBMITTER: Mishra JS

PROVIDER: S-EPMC6739159 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Estrogen Receptor-β Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression.

Mishra Jay S JS Te Riele Gigi M GM Qi Qian-Rong QR Lechuga Thomas J TJ Gopalakrishnan Kathirvel K Chen Dong-Bao DB Kumar Sathish S

Hypertension (Dallas, Tex. : 1979) 20190805 4

The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-β-dependent transcription in a pregnancy-spec ...[more]

PMID: 31378106

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Project description:Estradiol-17beta (E(2)beta) and its metabolites, which are sequentially synthesized by cytochrome P450s and catechol-O-methyltransferase to form 2 and 4-hydroxyestradiol (OHE(2)) and 2- and 4-methoxestradiol (ME(2)), are elevated during pregnancy. We investigated whether cytochrome P450s and catechol-O-methyltransferase are expressed in uterine artery endothelial cells (UAECs) and whether E(2)beta and its metabolites modulate cell proliferation via ER-alpha and/or ER-beta and play roles in physiological uterine angiogenesis during pregnancy. Cultured ovine UAECs from pregnant and nonpregnant ewes were treated with 0.1 to 100.0 nmol/L of E(2)beta, 2-OHE(2), 4-OHE(2), 2-ME(2), and 4-ME(2). ER-alpha or ER-beta specificity was tested using ICI 182 780, ER-alpha-specific 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinyleth oxy)phenol]-1H-pyrazole dihydrochloride, ER-beta-specific 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo [1,5-a]pyrim idin-3-yl]phenol antagonists and their respective agonists ER-alpha-specific 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol and ER-beta-specific 2,3-bis(4-Hydroxyphenyl)-propionitrile. Angiogenesis was evaluated using 5-bromodeoxyuridine proliferation assay. Using confocal microscopy and Western analyses to determine enzyme location and levels, we observed CYP1A1, CYP1A2, CYP1B1, CYP3A4, and catechol-O-methyltransferase expression in UAECs; however, expressions were similar between nonpregnant UAECs and pregnant UAECs. E(2)beta, 2-OHE(2), 4-OHE(2), and 4-ME(2) treatments concentration-dependently stimulated proliferation in pregnant UAECs but not in nonpregnant UAECs; 2-ME(2) did not stimulate proliferation in either cell type. Proliferative responses of pregnant UAECs to E(2)beta were solely mediated by ER-beta, whereas responses to E(2)beta metabolites were neither ER-alpha nor ER-beta mediated. We demonstrate an important vascular role for E(2)beta, its cytochrome P450- and catechol-O-methyltransferase-derived metabolites, and ER-beta in uterine angiogenesis regulation during pregnancy that may be dysfunctional in preeclampsia and other cardiovascular disorders.

Dataset Information

Estrogen Receptor-? Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression.

Publications

Estrogen Receptor-β Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression.

Similar Datasets

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