Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

项目总结(项目一) 妊娠期间子宫血流量的显著增加对于胎儿的最佳生长是必不可少的。 胎儿和母亲的心血管健康。子宫胎盘适应不良 妊娠期间的血液循环与临床并发症的高发生率有关，包括 子痫前期与胎儿宫内生长受限大电导钙激活钾 (BKCa)通道在调节妊娠期间子宫血流中起着关键作用。最近的研究 绵羊表明，怀孕和类固醇激素导致BKCa显著增加 β1亚基导致β1：亚基化学计量比增加和BKCa通道活性增加 在子宫动脉。妊娠期间的慢性缺氧消除了这些变化。然而，分子 机制仍不清楚。我们的初步研究表明，怀孕和类固醇 激素导致β-1基因启动子上的甲基化减少。DNA甲基化是一种 表观遗传抑制基因表达模式的主要机制，最近的研究表明 10-11易位1-3(TET1-3)蛋白在活性DNA中的强健机制 去甲基化。初步研究表明，怀孕和类固醇激素增加 Tet1-2在子宫动脉的表达。这些发现导致了对一种高度 验证类固醇激素诱导、表观遗传介导的假说的新机制 DNA甲基化和去甲基化的动态变化在基因表达调控中起着关键作用 以及BKCa通道在子宫血管适应妊娠和慢性缺氧中的作用。 三个特定的目标将决定：1)类固醇激素介导的启动子去甲基化 BKCaβ1基因上调在子宫BKCa通道功能增强中起因果作用 2)类固醇激素增加子宫TET1-3蛋白的表达 3)类固醇激素介导的TET1-3上调在活动性脑出血中起因果作用。 β-1基因在妊娠过程中的去甲基化和再激活结果将大大进步。 我们对子宫胎盘适应妊娠的分子机制的认识，并提高我们的 子宫胎盘适应不良的病理生理机制的认识 与慢性缺氧相关的循环和妊娠并发症。他们还将有一个 广泛影响对调节BKCa通道活性的分子机制的理解 生理和病理生理学中的血管功能。

PROJECT SUMMARY (Project I) The striking increase of uterine blood flow during pregnancy 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. Recent studies in sheep demonstrated that pregnancy and steroid hormones caused a significant increase in BKCa β1 subunit resulting in increased β1: subunit stoichiometry and heightened BKCa channel activity in uterine arteries. Chronic hypoxia during gestation abrogated these changes. Yet the molecular mechanisms remain unknown. Our preliminary studies 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. Preliminary studies suggested that pregnancy and steroid hormones increased TET1-2 expression in uterine arteries. These findings lead to the proposed studies of a highly novel mechanism testing the hypothesis that steroid hormone-induced, epigenetic-mediated dynamic changes of DNA methylation and 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 hormone-mediated promoter demethylation and BKca β1 gene up-regulation play a causal role in increased BKca channel function in uterine arteries in pregnancy, 2) steroid hormones increase the expression of TET1-3 proteins in uterine arteries, and 3) steroid hormone-mediated up-regulation of TET1-3 plays a causal role in active DNA demethylation and the β1 gene reactivation in pregnancy. 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 uteroplacental circulation and pregnancy complications associated with chronic hypoxia. They will also have a broad impact in understanding of molecular mechanisms in regulating BKca channel activity and vascular function in physiology and pathophysiology.