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11 January 2017 chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca2 -activated K channel function in ovine uterine arteries
Xiang-Qun Hu, Man Chen, Chiranjib Dasgupta, Daliao Xiao, Xiaohui Huang, Shumei Yang, Lubo Zhang
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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.

Summary Sentence

Gestational hypoxia promotes hypermethylation and repression of KCNMB1 gene and BKCa channel function in uterine arteries by upregulating DNMTexpression and activity, leading tomaladaptation of uterine circulation during pregnancy.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please journals.permissions@oup.com
Xiang-Qun Hu, Man Chen, Chiranjib Dasgupta, Daliao Xiao, Xiaohui Huang, Shumei Yang, and Lubo Zhang "chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca2 -activated K channel function in ovine uterine arteries," Biology of Reproduction 96(2), 424-434, (11 January 2017). https://doi.org/10.1095/biolreprod.116.145946
Received: 17 October 2016; Accepted: 19 December 2016; Published: 11 January 2017
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