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

Hypertension 2019 10 5;74(4):967-974. Epub 2019 Aug 5.

From the Department of Comparative Biosciences, School of Veterinary Medicine (J.S.M., G.M.t.R., K.G., S.K.), University of Wisconsin-Madison.

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

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739159PMC
October 2019
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