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Hypoxia Upregulates Estrogen Receptor ? in Pulmonary Artery Endothelial Cells in a HIF-1?-Dependent Manner.

ABSTRACT: 17?-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1? (HIF-1?)-dependent increases in ER? expression. Sprague-Dawley rats and ER? or ER? knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs). Hypoxia increased expression of ER?, but not ER?, in lungs from HPH rats as well as in rat and human PAECs. ER? mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1?/HIF-2? stabilization increased PAEC ER?, whereas HIF-1? knockdown decreased ER? abundance in hypoxic PAECs. In turn, ER? knockdown in hypoxic PAECs increased HIF-2? expression, suggesting a hypoxia-sensitive feedback mechanism. ER? knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ER? activation increased PHD2 and decreased both HIF-1? and HIF-2?, suggesting that ER? regulates the PHD2/HIF-1?/HIF-2? axis during hypoxia. Whereas hypoxic wild-type or ER? knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1? after hypoxia compared with untreated hypoxic mice, ER? knockout mice exhibited increased HIF-2? and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1?, increases ER? expression and the E2-ER? axis targets PHD2, HIF-1?, and HIF-2? to attenuate HPH development.

SUBMITTER: Frump AL

PROVIDER: S-EPMC6039879 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner.

Frump Andrea L AL Selej Mona M Wood Jordan A JA Albrecht Marjorie M Yakubov Bakhtiyor B Petrache Irina I Lahm Tim T

American journal of respiratory cell and molecular biology 20180701 1

17β-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague-Dawley rats and ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2 ...[more]

PMID: 29394091

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Project description: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.

Dataset Information

Hypoxia Upregulates Estrogen Receptor ? in Pulmonary Artery Endothelial Cells in a HIF-1?-Dependent Manner.

Publications

Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner.

Similar Datasets

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