Epigenetic mechanisms of uterine vascular adaptation to pregnancy and hypoxia

子宫血管适应妊娠和缺氧的表观遗传机制

• 批准号: 9242047
• 负责人: Lubo Zhang
• 金额: $ 39.5万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242047
• 关键词: 3' Untranslated Regions; Adult; Altitude; Arteries; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular system; Chronic; Clinical; Clinical Management; Complex; DNA; DNA Methylation; Data; Down-Regulation; Employee Strikes; Epigenetic Process; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Gene-Modified; Genes; Genetic Translation; Growth; Hormones; Hypoxia; Incidence; Knowledge; Maternal Health; Measures; Mediating; Messenger RNA; Methylation; MicroRNAs; Molecular; Mothers; Physiology; Play; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Promoter Regions; Proteins; Regulation; Research; Role; Sea; Series; Sheep; Testing; Tissues; Translations; Up-Regulation; Uteroplacental Circulation; Vascular Smooth Muscle; demethylation; epigenetic regulation; experimental study; fetal; gene repression; improved; insight; neonatal outcome; novel; perinatal morbidity; pregnant; pressure; promoter; public health relevance; steroid hormone; stoichiometry; vascular bed; virtual

 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.

 描述（由适用提供）：子宫血流在怀孕期间显着增加，这对于胎儿的最佳生长和母亲的心血管福祉至关重要。妊娠期间子宫道循环的适应不良与临床并发症的高发病率有关，包括先兆子痫和胎儿内生长限制。大型CA2+激活的K+（BKCA）通道在调节血管平滑肌中子宫BKCA通道方面起着至关重要的作用，其中包含形成通道的α亚基和多达四个辅助β1亚基，可增强BKCA通道的CA2+敏感性。先前的绵羊研究表明，妊娠和类固醇恐怖导致BKCAβ1亚基的显着增加，导致β1：α亚基化学计量法和子宫动脉中BKCA通道活性的增强。重要的是，妊娠期间的慢性缺氧废除了这些变化。然而，分子机制仍然未知。我们最近的研究表明，妊娠和定型激素在β1基因启动子处导致DNA甲基化降低。 DNA甲基化是表观遗传表达模式中的主要机制，最近的研究表明，活性DNA脱甲基化中十倍的易位1-3（TET1-3）蛋白的强大机制。我们的初步研究表明，妊娠和类固醇恐怖增加了子宫动脉中TET1-2的表达。此外，初步数据表明，妊娠期间的慢性缺氧导致子宫动脉中microRNA 210（miR210）的显着增加，该动脉的靶向TET1 mRNA 3'UTR并对其翻译负面调节。凭借这些令人兴奋的发现和许多新颖的潜在客户，我们可以通过推出新的和范式转移的研究重点来显着推动该领域，并测试MiR210的分子和表观遗传机制与TET介导的DNA脱甲基化相互作用的假说，在调节BKCACCACCAPTIAN和CHASTELS中的功能在utascation and utastical and primpation中起关键作用。 Three specific aims will determine whether: 1) Steroid horrmones upregulate TET gene expression leading to DNA demethylation and increased BKca β1 gene expression in uterine artefact in pregnancy, 2) chronic hypoxia during gestation increases miR210 inhibition TET mRNA translation and abrogates steroid hormone-mediated upregulation of BKca β1 gene expression in uterine artefact, and 3) determine the miR210和TET介导的脱甲基在调节子宫伪像的BKCA通道功能中的因果作用。结果将显着提高我们在适应妊娠的子宫分子机制方面的知识，并提高我们对子宫牙科循环疾病疾病的病理生理机制的理解，与慢性低氧相关的妊娠并发症。他们还将在对BKCA通道活性和病理生理学中总体上的BKCA通道活性和血管功能中的分子机制的理解中产生广泛的影响。