Epigenetic mechanisms of uterine vascular adaptation to pregnancy and hypoxia

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Uterine blood flow increases significantly during pregnancy, which is essential both for optimal growth of the fetus and cardiovascular well-being of the mother. Maladaptation of the uteroplacental circulation during gestation is associated with high incidence of clinical complications including preeclampsia and fetal intrauterine growth restriction. Large-conductance Ca2+-activated K+ (BKca) channels play a critical role in regulating uterine blood flow in pregnancy. The BKca channel in vascular smooth muscle contains the channel-forming α subunit and up to four accessory β1 subunits that enhance the Ca2+ sensitivity of BKca channels. Previous studies in sheep demonstrated that pregnancy and steroid hormones caused a significant increase in BKCa β1 subunit resulting in increased β1: α subunit stoichiometry and heightened BKCa channel activity in uterine arteries. Of importance, chronic hypoxia during gestation abrogated these changes. Yet the molecular mechanisms remain unknown. Our recent study showed that pregnancy and steroid hormones caused a decrease in DNA methylation at the β1 gene promoter. DNA methylation is a chief mechanism in epigenetic repression of gene expression patterns, and recent studies suggest a robust mechanism of ten-eleven translocation 1-3 (TET1-3) proteins in active DNA demethylation. Our preliminary studies suggested that pregnancy and steroid hormones increased TET1-2 expression in uterine arteries. Furthermore, the preliminary data demonstrated that chronic hypoxia during gestation resulted in a significant increase in microRNA 210 (miR210) in uterine arteries, which targeted TET1 mRNA 3'UTR and negatively regulated its translation. With these exciting findings and many highly novel leads, we are positioned to move the field forward significantly in a manner by launching a new and paradigm-shifting focus of research and to test the hypothesis that molecular and epigenetic mechanisms of miR210 interacting with TET-mediated DNA demethylation play a key role in regulating expression and function of BKca channels in uterine vascular adaptation to pregnancy and chronic hypoxia. Three specific aims will determine whether: 1) steroid hormones upregulate TET gene expression leading to DNA demethylation and increased BKca β1 gene expression in uterine arterial adaptation to pregnancy, 2) chronic hypoxia during gestation increases miR210 inhibiting TET mRNA translation and abrogates steroid hormone-mediated upregulation of BKca β1 gene expression in uterine arteries, and 3) determine the causal effect of miR210 and TET-mediated demethylation in regulating BKca channel function in uterine arterial adaptation to pregnancy and hypoxia. The results will significantly advance our knowledge in molecular mechanisms of uteroplacental adaptation to pregnancy and improve our understanding of pathophysiological mechanisms underlying maladaptation of the uteroplacental circulation and pregnancy complications associated with chronic hypoxia. They also will have a broad impact in the understanding of molecular mechanisms in regulating BKca channel activity and vascular function in general in physiology and pathophysiology.