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DNA methylation contributes to chronic hypoxia‐induced downregulation of large‐conductance Ca 2+ ‐activated K + channels in uterine arteries in pregnancy (889.3)
Author(s) -
Hu XiangQun,
Zhu Ronghui,
Zhang Lubo
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.889.3
Subject(s) - downregulation and upregulation , hypoxia (environmental) , dna methylation , endocrinology , estrogen , medicine , chemistry , methylation , dna , gene expression , oxygen , biochemistry , organic chemistry , gene
Uterine blood flow increases dramatically during pregnancy in part due to an upregulation of the large‐conductance Ca 2+ ‐activated K + (BK Ca ) channel in the uterine artery. However, this hemodynamic change is complicated by chronic hypoxia. We hypothesized that DNA methylation may play a role in chronic hypoxia‐induced downregulation of BK Ca channels. Uterine arteries were isolated from nonpregnant (NPUA) and near‐term (~140 days) pregnant (PUA) sheep and incubated under 21% or 10.5% O 2 for 48 hours at 37°C. Exposure to chronic hypoxia significantly reduced the BK Ca current density in PUA ( p < 0.05), but not in NPUA. 5‐aza‐2'‐deoxycytidine (5‐aza), a DNA methylation inhibitor, blocked the hypoxia‐mediated effect in PUA. Accordingly, chronic hypoxia decreased a BK Ca activator NS 1619‐induced relaxations of PUA, which was abrogated by 5‐aza. Treatment of NPUA ex vivo under 21% O 2 with physiological concentrations of estrogen and progesterone (E2β/P4) resulted in increased BK Ca current density; and chronic hypoxia suppressed this upregulation. However, 5‐aza reversed the impact of chronic hypoxia and restored the ability of E2β/P4 in upregulating the BK Ca current density. Taken together, our findings suggest that an epigenetic modification of DNA methylation plays an important role in chronic hypoxia‐induced downregulation of BK Ca channel function in uterine arteries in pregnancy. Grant Funding Source : HL089012, HL110125