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.
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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DOI：
10.1161/hypertensionaha.115.05299
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
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作者：
Chen M;Xiao D;Hu XQ;Dasgupta C;Yang S;Zhang L
以往的体内研究表明，妊娠期慢性缺氧与绵羊子宫动脉中雌激素受体α基因的抑制有关。然而，缺氧是否有直接影响以及DNA甲基化是否在缺氧介导的雌激素受体-α基因抑制中起因果作用仍然不确定。因此，本研究验证了这一假设，即长时间缺氧具有直接作用，并增加启动子甲基化，导致雌激素受体-α基因抑制和雌激素介导的子宫血管张力适应性抑制。用21.0%O_2和10.5%O_2离体处理非妊娠和妊娠绵羊的子宫动脉48小时。缺氧显著增加雌激素受体-α启动子Sp1和USF结合位点的甲基化，降低Sp1和USF与启动子的结合，抑制妊娠动物子宫动脉中雌激素受体-α的表达。重要的是，缺氧的影响被甲基化抑制剂5-氮杂-2 ′-脱氧胞苷阻断。此外，缺氧可抑制类固醇激素介导的雌激素受体α表达的增加，抑制类固醇激素诱导的大电导钙激活钾通道活性的增加和非妊娠动物子宫动脉肌源性张力的降低，并可被5-氮-2 ′-脱氧胞苷逆转。结果提供了新的证据表明，缺氧对启动子甲基化的直接影响，在雌激素受体-α基因的抑制和类固醇激素介导的子宫动脉大电导钙激活K+通道活性和肌源性张力的适应性消融中发挥因果作用。
Previous in vivo study demonstrated that chronic hypoxia during gestation was associated with estrogen receptor-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 estrogen receptor-α gene repression. Thus, the present study tested the hypothesis that prolonged hypoxia has a direct effect and increases promoter methylation resulting in estrogen receptor-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 estrogen receptor-α promoter methylation at both Sp1 and USF binding sites, decreased Sp1 and USF binding to the promoter and suppressed estrogen receptor-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 estrogen receptor-α expression, and inhibited the hormone-induced increase in large conductance Ca2+-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 estrogen receptor-α gene repression and ablation of steroid hormone-mediated adaptation of uterine arterial large conductance Ca2+-activated K+ channel activity and myogenic tone in pregnancy.