Mechanisms of uterine artery hemodynamics adaptation to pregnancy and gestational hypoxia

子宫动脉血流动力学适应妊娠及妊娠缺氧的机制

• 批准号: 10707721
• 负责人: Arlin B Blood
• 金额: $ 80.75万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707721
• 关键词: Acclimatization; Adverse effects; Altitude; Animal Model; Arteries; Binding; Blood Pressure; Blood Vessels; Blood flow; Cardiac Myocytes; Cardiovascular system; Chronic; Clinical; Communication; Down-Regulation; Epigenetic Process; Estrogens; Exposure to; Fetal Development; Fetal Growth Retardation; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Gonadal Steroid Hormones; Human; Hypoxia; Incidence; L-type calcium channel alpha(1C); Maternal Health; Measurement; Mediating; Methylation; MicroRNAs; Mitochondria; Molecular; Monomeric GTP-Binding Proteins; Mothers; Muscle Contraction; Organ; Pathway interactions; Perinatal mortality demographics; Personal Satisfaction; Phenotype; Physiology; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant Women; Pregnant sheep; Production; Quantitative Reverse Transcriptase PCR; RRAD gene; Regulation; Research; Resistance; Response Elements; Role; Sea; Sheep; Systemic blood pressure; Testing; Translations; Up-Regulation; Uterus; Vascular Smooth Muscle; Vascular resistance; fetal; gestational hypoxia; hemodynamics; improved; in vivo; insight; interest; knock-down; neonatal outcome; novel; perinatal morbidity; pharmacologic; pressure; programs; promoter; protein expression; response; transcriptome sequencing; vascular bed; vasoconstriction; virtual

Project Summary Pregnancy is associated with a striking increase of uterine blood flow that is essential for normal fetal development as well as for cardiovascular well-being of the mother. Hypoxia during pregnancy has profound adverse effects on uterine artery hemodynamics adaptation, increasing incidence of pregnancy complications including preeclampsia and fetal intrauterine growth restriction. Previous studies in an animal model of pregnant sheep acclimatized to high altitude hypoxia demonstrated that pregnant ewes were similar to pregnant women in that they both showed an increase in uterine vascular resistance and elevation in maternal systemic blood pressure in response to gestational hypoxia. Yet, much remains unknown of the mechanisms underlying maternal cardiovascular maladaptation to chronic hypoxia during pregnancy. Our preliminary study in sheep suggests a highly novel mechanism of a monomeric G protein, Rad in inhibition of L-type CaV1.2 calcium channel currents in the uterine artery. The L-type CaV1.2 calcium channel, as the major pathway of Ca2+ influx, is essential for vascular smooth muscle contractions and plays a central role in regulating organ blood flow and arterial pressure. We identify that both ovine and human Rad gene promoters have multiple estrogen response elements (EREs), suggesting a robust mechanism of sex steroid hormones in the regulation of Rad gene expression in the uterine artery. In addition, the approach of RNA-seq analysis revealed a downregulation of Rad gene expression in uterine arteries of pregnant ewes acclimatized to high altitude hypoxia. Of importance, we demonstrated that chronic hypoxia during gestation abrogated pregnancy-induced upregulation of Rad protein expression and increased CaV1.2 channel currents in ovine uterine arteries. These exciting findings and many highly novel leads provide a strong scientific premise for us to move the field forward significantly by launching a new focus of research aimed at understanding the molecular and epigenetic mechanisms of Rad in regulating CaV1.2 channel currents and phenotypic programming of uterine vascular adaptation to pregnancy and gestational hypoxia. The proposed study will be conducted in a unique animal model of pregnant sheep exposed to high altitude (3801 m/12,470 ft) hypoxia during gestation. The overall hypothesis of the proposed study is that Rad is a novel regulatory mechanism and plays an essential role in the regulation of L-type CaV1.2 calcium channel currents and uterine vascular adaptation to pregnancy and gestational hypoxia. The proposed study has the strong scientific premise with a novel conceptual framework and mechanistic approach. It will provide new insights into fundamental mechanisms in uterine vascular adaptation to pregnancy, and will have a major impact on our understanding of pathophysiologic mechanisms underlying pregnancy complications including preeclampsia caused by gestational hypoxia. Of importance, the similarity in uterine artery hemodynamics and maternal blood pressure responses to gestational hypoxia between pregnant ewes and pregnant women, as well as likely common mechanisms of Rad gene regulation by sex steroid hormones, will provide much needed translational relevance of the proposed study in the understanding of maternal cardiovascular complications in response to hypoxia during pregnancy.

项目摘要 怀孕与子宫血流量的显着增加有关，这对正常胎儿至关重要 发展以及心血管健康的母亲。怀孕期间的缺氧有很深的 不良影响子宫动脉血流动力学适应，增加妊娠并发症发生率 包括先兆子痫和胎儿宫内生长受限。先前在妊娠动物模型中的研究 绵羊高原低氧习服表明，妊娠母羊与妊娠妇女相似 因为它们都显示子宫血管阻力增加和母体全身血液升高 妊娠缺氧时的血压然而，许多潜在的机制仍然未知 母体心血管对妊娠期慢性缺氧的适应不良。我们对绵羊的初步研究 提出了单体G蛋白Rad抑制L型CaV1.2钙通道的一种非常新颖的机制 子宫动脉中的电流L型CaV1.2钙通道作为Ca 2+内流的主要通道，在心肌细胞中起重要作用 血管平滑肌收缩，并在调节器官血流和动脉 压力我们发现绵羊和人类的Rad基因启动子都有多个雌激素反应元件 （ERE），表明性类固醇激素在调节Rad基因表达中存在强大的机制。 子宫动脉此外，RNA-seq分析的方法揭示了Rad基因的下调 在高原低氧习服妊娠母羊子宫动脉中的表达。重要的是，我们 结果表明，妊娠期间慢性缺氧消除了妊娠诱导的Rad蛋白上调， 表达和增加绵羊子宫动脉中CaV1.2通道电流。这些令人兴奋的发现和许多 高度新颖的线索为我们提供了一个强有力的科学前提，通过启动 一个新的研究重点，旨在了解分子和表观遗传机制的拉德在调节 CaV1.2通道电流和子宫血管对妊娠适应的表型编程 妊娠缺氧拟定研究将在妊娠绵羊暴露的独特动物模型中进行 高海拔（3801米/12，470英尺）缺氧。拟议研究的总体假设是， Rad是一种新的调节机制，在L型CaV 1.2钙的调节中起重要作用 通道电流和子宫血管对妊娠和妊娠缺氧的适应。拟定研究 具有很强的科学前提，具有新颖的概念框架和机械方法。它将提供 新的见解，在子宫血管适应怀孕的基本机制，并将有一个重大的 对我们理解妊娠并发症的病理生理机制的影响，包括 妊娠缺氧引起的先兆子痫重要的是，子宫动脉血流动力学和 妊娠母羊和妊娠妇女之间母体血压对妊娠缺氧的反应， 以及性类固醇激素对Rad基因调控的可能共同机制，将提供急需的 拟议研究在理解母体心血管并发症方面的翻译相关性 怀孕期间的缺氧反应。