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Hypoxia Represses ER-? Expression and Inhibits Estrogen-Induced Regulation of Ca2+-Activated K+ Channel Activity and Myogenic Tone in Ovine Uterine Arteries: Causal Role of DNA Methylation.

ABSTRACT: Previous in vivo study demonstrated that chronic hypoxia during gestation was associated with estrogen receptor-? (ER-?) gene repression in ovine uterine arteries. Yet, it remains undetermined whether hypoxia had a direct effect and if DNA methylation played a causal role in hypoxia-mediated ER-? gene repression. Thus, this study tested the hypothesis that prolonged hypoxia has a direct effect and increases promoter methylation resulting in ER-? gene repression and inhibition of estrogen-mediated adaptation of uterine vascular tone. Uterine arteries isolated from nonpregnant and pregnant sheep were treated ex vivo with 21.0% O2 and 10.5% O2 for 48 hours. Hypoxia significantly increased ER-? promoter methylation at both specificity protein-1 and upstream stimulatory factor binding sites, decreased specificity protein-1 and upstream stimulatory factor binding to the promoter, and suppressed ER-? expression in uterine arteries of pregnant animals. Of importance, the effects of hypoxia were blocked by a methylation inhibitor 5-aza-2'-deoxycytidine. In addition, hypoxia abrogated steroid hormone-mediated increase in ER-? expression and inhibited the hormone-induced increase in large-conductance Ca(2+)-activated K(+) channel activity and decrease in myogenic tone in uterine arteries of nonpregnant animals, which were reversed by 5-aza-2'-deoxycytidine. The results provide novel evidence of a direct effect of hypoxia on heightened promoter methylation that plays a causal role in ER-? gene repression and ablation of steroid hormone-mediated adaptation of uterine arterial large conductance Ca(2+)-activated K(+) channel activity and myogenic tone in pregnancy.

SUBMITTER: Chen M

PROVIDER: S-EPMC4465851 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Hypoxia Represses ER-α Expression and Inhibits Estrogen-Induced Regulation of Ca2+-Activated K+ Channel Activity and Myogenic Tone in Ovine Uterine Arteries: Causal Role of DNA Methylation.

Chen Man M Xiao Daliao D Hu Xiang-Qun XQ Dasgupta Chiranjib C Yang Shumei S Zhang Lubo L

Hypertension (Dallas, Tex. : 1979) 20150518 1

Previous in vivo study demonstrated that chronic hypoxia during gestation was associated with estrogen receptor-α (ER-α) gene repression in ovine uterine arteries. Yet, it remains undetermined whether hypoxia had a direct effect and if DNA methylation played a causal role in hypoxia-mediated ER-α gene repression. Thus, this study tested the hypothesis that prolonged hypoxia has a direct effect and increases promoter methylation resulting in ER-α gene repression and inhibition of estrogen-mediate ...[more]

PMID: 25987666

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Dataset Information

Hypoxia Represses ER-? Expression and Inhibits Estrogen-Induced Regulation of Ca2+-Activated K+ Channel Activity and Myogenic Tone in Ovine Uterine Arteries: Causal Role of DNA Methylation.

Publications

Hypoxia Represses ER-α Expression and Inhibits Estrogen-Induced Regulation of Ca2+-Activated K+ Channel Activity and Myogenic Tone in Ovine Uterine Arteries: Causal Role of DNA Methylation.

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