DNA Demethylation and BKca Channel Expression and Function in Uterine Arteries

子宫动脉中 DNA 去甲基化和 BKca 通道表达和功能

• 批准号: 8858032
• 负责人: Lubo Zhang
• 金额: $ 23.7万
• 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: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858032
• 关键词: Adult; Arteries; Blood Vessels; Blood flow; Cardiovascular system; Clinical; Clinical Management; DNA; DNA Methylation; Down-Regulation; Employee Strikes; Epigenetic Process; Fetal Development; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression Profile; Genes; Growth; Hormones; Hydroxylation; Incidence; Investigation; Knowledge; Lead; Maternal Health; Mediating; Methylation; Modification; Molecular; Morbidity - disease rate; Mothers; Muscle function; Neonatal; Outcome; Perinatal; Personal Satisfaction; Physiology; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Promoter Regions; Proteins; Repression; Research; Role; Series; Sheep; Testing; Time; Tissues; Up-Regulation; Uteroplacental Circulation; Vascular Smooth Muscle; demethylation; epigenetic regulation; fetal; gene repression; improved; inhibitor/antagonist; innovation; insight; novel; pregnant; pressure; promoter; public health relevance; research study; steroid hormone; stoichiometry; vascular bed

 DESCRIPTION (provided by applicant): 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 development abnormality. 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:α subunit stoichiometry and heightened BKCa channel activity in uterine arteries. 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. 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-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. Two 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, and 2) steroid hormone-mediated up-regulation of TET1-3 plays a causal role in active DNA demethylation and the β1 gene up-regulation in pregnancy. The proposed study presents a major breakthrough and paradigm-shifting focus of research aiming at unraveling highly novel epigenetic mechanisms of hormone-mediated DNA demethylation in regulating gene expression patterns in uterine vasculature in particular, and in vascular smooth muscle function in general. The outcome of the proposed study 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. Because of the vital importance of BKCa channel function in regulating vascular tone and pressure in virtually all vascular beds, and the extremely limited knowledge in epigenetic regulation of BKCa channel expression and activity in vascular smooth muscle, the proposed study will indeed have a much broad impact in comprehensive understanding of molecular mechanisms in regulating BKCa channel activity and vascular function in physiology and pathophysiology.

 描述（由申请人提供）：怀孕期间子宫血流量的显着增加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子痫前期和胎儿发育异常等临床并发症的高发生率有关。大电导 Ca2+ 激活 K+ (BKCa) 通道在妊娠期子宫血流调节中发挥着关键作用。最近对绵羊的研究表明，怀孕和类固醇激素导致 BKCa β1 亚基显着增加，导致 β1:α 亚基化学计量增加，并增强子宫动脉中的 BKCa 通道活性。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 β1 基因启动子处的 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，10-11 易位 1-3 (TET1-3) 蛋白在主动 DNA 去甲基化中存在强大的机制。初步研究表明怀孕和类固醇激素会增加子宫动脉中 TET1-2 的表达。这些发现引发了对一种高度新颖的机制的研究，该机制测试了以下假设：类固醇激素介导的 DNA 甲基化和去甲基化的动态变化在调节 BKCa 通道的表达和功能在子宫血管适应妊娠中发挥着关键作用。两个具体目标将确定：1）类固醇激素介导的启动子去甲基化和 BKCa β1 基因上调在妊娠期子宫动脉 BKCa 通道功能增强中起因果作用；2）类固醇激素介导的 TET1-3 上调在妊娠期主动 DNA 去甲基化和 β1 基因上调中起因果作用。这项研究提出了一项重大突破和范式转变的研究重点，旨在揭示激素介导的 DNA 去甲基化在调节子宫脉管系统基因表达模式以及一般血管平滑肌功能中的高度新颖的表观遗传机制。这项研究的结果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适应不良和妊娠并发症的病理生理机制的理解。由于 BKCa 通道功能在调节几乎所有血管床的血管张力和压力中至关重要，并且对血管平滑肌中 BKCa 通道表达和活性的表观遗传调节的了解极其有限，因此本研究确实将对生理学和病理生理学中调节 BKCa 通道活性和血管功能的分子机制的全面理解产生广泛的影响。