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: 9096200
• 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/9096200
• 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; Genes; Genetic Translation; Growth; Health; Hormones; Hypoxia; Incidence; Knowledge; Maternal Health; Measures; Mediating; Messenger RNA; Methylation; MicroRNAs; Modification; Molecular; Mothers; Personal Satisfaction; Physiology; Play; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Promoter Regions; Proteins; Regulation; Repression; Research; Role; Sea; Series; Sheep; Testing; Tissues; Translations; Untranslated Regions; Up-Regulation; Uteroplacental Circulation; Vascular Smooth Muscle; demethylation; epigenetic regulation; fetal; gene repression; improved; insight; neonatal outcome; novel; perinatal morbidity; pregnant; pressure; promoter; research study; steroid hormone; stoichiometry; vascular bed

 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（由申请人提供）：妊娠期间子宫血流量显着增加，这对于胎儿的最佳生长和母亲的心血管健康至关重要。妊娠期间子宫胎盘循环的适应不良与临床并发症的高发生率有关，包括。先兆子痫和胎儿宫内生长受限。大电导 Ca2+ 激活的 K+ (BKca) 通道在妊娠期子宫血流调节中发挥着关键作用。血管平滑肌中的 BKca 通道包含通道形成 α 亚基和最多四个辅助 β1 亚基，可增强 BKca 通道的 Ca2+ 敏感性。先前的研究表明，妊娠和类固醇激素导致 BKCa β1 亚基显着增加。 β1：α亚基化学计量和子宫动脉中广泛的 BKCa 通道活性重要的是，妊娠期间的慢性缺氧消除了这些变化，但其分子机制仍不清楚。我们最近的研究表明，怀孕和类固醇激素导致 β1 基因启动子处 DNA 甲基化减少，DNA 甲基化是基因表达模式表观遗传抑制的主要机制，最近的研究表明存在 10-11 易位 1-3 的强大机制。我们的初步研究表明，妊娠和类固醇激素会增加子宫动脉中的 TET1-2 表达。此外，初步数据表明，妊娠期间的慢性缺氧会导致子宫动脉中的 microRNA 210 (miR210) 显着增加，其靶向 TET1 mRNA 3'UTR 并负向调节其翻译。凭借这些令人兴奋的发现和许多高度新颖的线索，我们有能力通过启动一项新的研究，以某种方式显着推动该领域向前发展。新的、范式转移的研究焦点，并检验以下假设：miR210 的分子和表观遗传机制与 TET 介导的 DNA 去甲基化相互作用在调节 BKca 通道的表达和功能中发挥关键作用。子宫血管适应妊娠和慢性缺氧的三个具体目标将决定是否：1）类固醇激素上调 TET 基因表达，导致子宫动脉适应妊娠过程中 DNA 去甲基化和 BKca β1 基因表达增加，2）妊娠期间慢性缺氧增加 miR210 抑制。 TET mRNA 翻译并消除子宫动脉中类固醇激素介导的 BKca β1 基因表达上调，以及 3) 确定miR210 和 TET 介导的去甲基化在调节子宫动脉适应妊娠和缺氧过程中的 BKca 通道功能将显着提高我们对子宫胎盘适应妊娠的分子机制的认识，并提高我们对子宫胎盘循环和妊娠适应不良的病理生理机制的理解。它们还将对理解调节 BKca 通道活性和一般生理学血管功能的分子机制产生广泛的影响。和病理生理学。