title: Chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca2+-activated K+ channel function in ovine uterine arteries.
abstract: Chronic hypoxia during gestation suppresses large-conductance Ca2+-activated K+ (BKCa) channel function and impedes uterine arterial adaptation to pregnancy. This study tested the hypothesis that chronic hypoxia has a direct effect in upregulating DNA methyltransferase (DNMT) and epigenetically repressing BKCa channel beta-1 subunit (KCNMB1) expression in uterine arteries. Resistance-sized uterine arteries were isolated from near-term pregnant sheep maintained at ∼300 m above sea level or animals acclimatized to high-altitude (3,801 m) hypoxia for 110 days during gestation. For ex vivo hypoxia treatment, uterine arteries from normoxic animals were treated with 21.0% O2 or 10.5% O2 for 48 h. High-altitude hypoxia significantly upregulated DNMT3b expression and enzyme activity in uterine arteries. Similarly, ex vivo hypoxia treatment upregulated DNMT3b expression and enzyme activity that was blocked by a DNMT inhibitor 5-aza-2'-deoxycytidine (5-Aza). Of importance, 5-Aza inhibited hypoxia-induced hypermethylation of specificity protein (SP) 1 binding site at the KCNMB1 promoter and restored transcription factor binding to the KCNMB1 promoter, resulting in the recovery of KCNMB1 gene expression in uterine arteries. Furthermore, 5-Aza blocked the effect of hypoxia and rescued BKCa channel activity and reversed hypoxia-induced decrease in BKCa channel-mediated relaxations and increase in myogenic tone of uterine arteries. Collectively, these results suggest that chronic hypoxia during gestation upregulates DNMT expression and activity, resulting in hypermethylation and repression of KCNMB1 gene and BKCa channel function, impeding uterine arterial adaptation to pregnancy.
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Hu
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Chemistry and Biochemistry, California State University, San Bernardino, California, USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Yang
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000531:Altitude; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D000077209:Decitabine; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D024681:Potassium Channels, Calcium-Activated; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine
keywords: hypoxia; DNA methylation; BKCa channel; myogenic tone; uterine arteries