title: 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.
abstract: 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-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-α 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-α 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-α 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-α 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.
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Hu
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
authors.forename: Shumei
authors.initials: S
authors.lastname: Yang
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (M.C., D.X., X-.Q.H., C.D., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.). lzhang@llu.edu.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics* / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species; D012756:Sheep; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism*; D014655:Vascular Resistance
chemical_list: D047628:Estrogen Receptor alpha; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D017382:Reactive Oxygen Species; D011374:Progesterone; D004958:Estradiol; D000077209:Decitabine; D001374:Azacitidine; D000111:Acetylcysteine
keywords: DNA methylation; gene expression; gonadal steroid hormones; pregnancy