Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

子宫血管对妊娠的适应和慢性缺氧

• 批准号: 9072343
• 负责人: Lubo Zhang
• 金额: $ 19.15万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072343
• 关键词: Adult; Altitude; Arteries; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular system; Chronic; Clinical; Complex; DNA; DNA Methylation; Down-Regulation; Employee Strikes; Epigenetic Process; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Growth; Hormones; Hydroxylation; Hypoxia; Incidence; Knowledge; Lead; Mediating; Methylation; Modification; Molecular; Mothers; Personal Satisfaction; Physiology; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Promoter Regions; Proteins; Repression; Role; Sea; Series; Sheep; Testing; Tissues; Up-Regulation; Uteroplacental Circulation; Vascular Smooth Muscle; demethylation; developmental plasticity; epigenetic regulation; fetal; gene repression; improved; inhibitor/antagonist; novel; pregnant; pressure; promoter; research study; steroid hormone; stoichiometry; vascular bed

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.

项目概要（项目一） 怀孕期间子宫血流量的显著增加对于子宫的最佳生长和发育都是必不可少的。 胎儿和母亲的心血管健康。子宫胎盘适应不良 妊娠期间的循环与临床并发症的高发生率相关，包括 先兆子痫和胎儿宫内生长受限。大电导钙激活钾离子 （BKca）通道在妊娠期调节子宫血流中起关键作用。的近期研究 绵羊证明妊娠和类固醇激素引起BKCa显著增加， β1亚基导致β1：β 2亚基化学计量增加和BKCa通道活性升高 在子宫动脉中。妊娠期慢性缺氧可消除这些变化。然而， 机制仍然未知。我们的初步研究表明怀孕和类固醇 激素导致β1基因启动子DNA甲基化降低。DNA甲基化是 基因表达模式的表观遗传抑制的主要机制，最近的研究表明， 活性DNA中10 - 11易位1-3（TET 1 -3）蛋白的一种稳健机制 去甲基化初步研究表明，怀孕和类固醇激素增加 子宫动脉中TET 1 -2的表达。这些发现导致了一个高度的拟议研究 新的机制测试的假设，类固醇激素诱导的，表观遗传介导的 DNA甲基化和去甲基化的动态变化在调控表达中起关键作用 以及BKca通道在子宫血管对妊娠和慢性缺氧适应中的作用。 三个具体的目标将决定是否：1）类固醇激素介导的启动子去甲基化 BKca β1基因表达上调是子宫内膜BKca通道功能增强的原因 2）类固醇激素增加子宫内膜中TET 1 -3蛋白的表达 3）类固醇激素介导的TET 1 -3的上调在动脉粥样硬化的活动中起着因果作用。 妊娠期DNA去甲基化与β1基因再激活结果将大大推进 我们在子宫胎盘适应妊娠的分子机制方面的知识， 了解子宫胎盘适应不良的病理生理机制 与慢性缺氧相关的循环和妊娠并发症。他们也将有一个 对理解调节BKca通道活性的分子机制产生广泛影响， 生理学和病理生理学中的血管功能。