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

摘要

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