Hu Xiang-Qun, Dasgupta Chiranjib, Xiao Daliao, Huang Xiaohui, Yang Shumei, Zhang Lubo
From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
Hypertension. 2017 Jul 24. doi: 10.1161/HYPERTENSIONAHA.117.09864.
Gestational hypoxia inhibits large conductance Ca-activated K (BK) channel expression and function in uterine arterial adaptation to pregnancy. Given the findings that microRNA-210 (miR-210) is increased in hypoxia during gestation and preeclampsia, the present study sought to investigate the role of miR-210 in the regulation of BK channel adaptation in the uterine artery. Gestational hypoxia significantly increased uterine vascular resistance and blood pressure in pregnant sheep and upregulated miR-210 in uterine arteries. MiR-210 bound to ovine ten-eleven translocation methylcytosine dioxygenase 1 mRNA 3' untranslated region and decreased ten-eleven translocation methylcytosine dioxygenase 1 mRNA and protein abundance in uterine arteries of pregnant sheep, as well as abrogated steroid hormone-induced upregulation of ten-eleven translocation methylcytosine dioxygenase 1 expression in uterine arteries of nonpregnant animals. In accordance, miR-210 blocked pregnancy- and steroid hormone-induced upregulation of BK channel β1 subunit expression in uterine arteries. Functionally, miR-210 suppressed BK channel current density in uterine arterial myocytes of pregnant sheep and inhibited steroid hormone-induced increases in BK channel currents in uterine arteries of nonpregnant animals. Blockade of endogenous miR-210 inhibited hypoxia-induced suppression of BK channel activity. In addition, miR-210 decreased BK channel-mediated relaxations and increased pressure-dependent myogenic tone of uterine arteries. Together, the results demonstrate that miR-210 plays an important role in the downregulation of ten-eleven translocation methylcytosine dioxygenase 1 and repression of BK channel function in uterine arteries, revealing a novel mechanism of epigenetic regulation in the maladaptation of uterine hemodynamics in gestational hypoxia and preeclampsia.
妊娠期缺氧会抑制子宫动脉适应妊娠过程中的大电导钙激活钾（BK）通道表达及功能。鉴于在妊娠和子痫前期缺氧状态下微小RNA-210（miR-210）水平升高，本研究旨在探讨miR-210在子宫动脉BK通道适应性调节中的作用。妊娠期缺氧显著增加了妊娠绵羊的子宫血管阻力和血压，并上调了子宫动脉中的miR-210。miR-210与绵羊的10-11易位甲基胞嘧啶双加氧酶1 mRNA的3'非翻译区结合，降低了妊娠绵羊子宫动脉中10-11易位甲基胞嘧啶双加氧酶1 mRNA和蛋白丰度，同时消除了类固醇激素诱导的未妊娠动物子宫动脉中10-11易位甲基胞嘧啶双加氧酶1表达的上调。相应地，miR-210阻断了妊娠和类固醇激素诱导的子宫动脉中BK通道β1亚基表达的上调。在功能上，miR-210抑制了妊娠绵羊子宫动脉肌细胞中的BK通道电流密度，并抑制了类固醇激素诱导的未妊娠动物子宫动脉中BK通道电流的增加。阻断内源性miR-210可抑制缺氧诱导的BK通道活性抑制。此外，miR-210降低了BK通道介导的子宫动脉舒张，并增加了子宫动脉的压力依赖性肌源性张力。总之，这些结果表明miR-210在下调10-11易位甲基胞嘧啶双加氧酶1以及抑制子宫动脉BK通道功能中起重要作用，揭示了妊娠期缺氧和子痫前期子宫血流动力学适应不良中表观遗传调控的新机制。
