Gestational Hypoxia and Programming of Maternal, Fetal and Newborn Vascular Function

妊娠期缺氧与母体、胎儿和新生儿血管功能的编程

• 批准号: 10188626
• 负责人: William J. Pearce
• 金额: $ 76.32万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188626
• 关键词: Acclimatization; Acute; Adverse effects; Altitude; Animal Model; Animals; Arteries; Biochemical; Birth; Blood Pressure; Blood Vessels; Blood flow; Cerebrovascular Circulation; Chronic; Clinical; Clinical Management; Development; Dioxygenases; Environment; Epigenetic Process; Fetal Development; Fetal Growth Retardation; Fetal health; Fetus; Functional disorder; Goals; Human; Hypoxia; Incidence; Infant; Intraventricular; Lung; Maternal Health; Maternal complication; Mediating; Membrane Potentials; MicroRNAs; Molecular; Mothers; Newborn Infant; Organism; Perinatal mortality demographics; Perinatal subependymal hemorrhage; Persistent Fetal Circulation Syndrome; Pharmacology; Physiological; Physiology; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant sheep; Pulmonary Vascular Resistance; Pulmonary artery structure; Regulation; Research; Risk; Role; Ryanodine Receptors; Sea; Sheep; Smooth Muscle Myocytes; Stress; Systemic blood pressure; Tissues; Up-Regulation; Uterus; Vascular Diseases; Vascular Smooth Muscle; Vascular resistance; base; cell type; cerebral artery; cerebrovascular; developmental plasticity; disorder risk; endoplasmic reticulum stress; epigenetic regulation; fetal; fetus hypoxia; gestational hypoxia; improved; innovation; insight; intraventricular hemorrhage; molecular subtypes; multidisciplinary; neonatal outcome; neonatal pulmonary hypertension; novel; perinatal morbidity; pregnant; pressure; response; vascular bed; virtual

The overall goal of this multiple PI application is to understand the basic cellular and molecular mechanisms underlying maternal, fetal and newborn vascular adaptation in response to high altitude, long-term hypoxia during gestation. Hypoxia is one of the most common and severe stresses to an organism's homeostatic mechanisms, and hypoxia during gestation has profound adverse effects on maternal health and developmental plasticity. Gestational hypoxia is associated with high incidence of clinical complications including preeclampsia and fetal intrauterine growth restriction (IUGR). Both human and animal studies have revealed a causative role of increased uterine vascular resistance and lowered uterine blood flow in preeclampsia and IUGR. Our recent studies revealed that high altitude hypoxia suppressed pregnancy-induced uterine arterial adaptation and increased uterine vascular resistance and systemic blood pressure in pregnant sheep. Infants born at high altitude show significantly increased risk of persistent pulmonary hypertension. We demonstrated that gestational hypoxia at high altitude elevated pulmonary vascular resistance and increased pulmonary artery pressure and pressure response to acute hypoxia in newborn lambs. In addition, fetal hypoxia negatively impacts cerebral vascular development and increases the risk of intraventricular hemorrhage in newborns. Hypoxic-mediated responses are highly integrated across many cell types; nonetheless, they are tissue specific. In many respects these responses differ significantly between the fetus and newborn, as well as between non-pregnant and pregnant states. Much remains unknown of the molecular mechanisms underlying programming of maternal, fetal and newborn vascular response to long-term hypoxia in gestation. The proposed study is broadly based, multidisciplinary, integrated project using physiological, pharmacological, cellular, biochemical, and molecular approaches to investigate the mechanisms underlying maternal uterine, and fetal and newborn pulmonary and cerebral vascular response to long-term hypoxia in gestation. Based on >25 years of research by our group, the proposed study will be conducted in sheep acclimatized to high altitude (3801 m/12,470 ft). The overall hypothesis is that high altitude, long-term hypoxia during gestation increases micro RNA-210 and endoplasmic reticulum (ER) stress, differentially regulating spontaneous transient outward currents (STOCs) in programming of maternal, fetal and newborn vascular response, impacting developmental plasticity and the subsequent risk for disease. The proposed study has strong scientific premise with a novel concept and an innovative and mechanistic approach. It will provide new insights into the understanding of fundamental mechanisms underlying programming of maternal, fetal and newborn vascular dysfunction caused by gestational hypoxia, impacting maternal health and developmental plasticity. Given that STOCs are fundamentally important in regulating vascular tone and blood flow in virtually all vascular beds, revealing molecular and epigenetic regulation of STOCs function in programming of vascular response to hypoxia will have broad impact in the comprehensive understanding of the mechanisms in vascular physiology and pathophysiology.

这种多重PI应用的总体目标是了解母体、胎儿和新生儿血管适应妊娠期间高海拔、长期缺氧的基本细胞和分子机制。缺氧是对生物体稳态机制最常见和最严重的应激之一，妊娠期间缺氧对孕产妇健康和发育可塑性产生深远的不利影响。妊娠期缺氧与子痫前期和胎儿宫内生长受限（IUGR）等临床并发症的高发生率有关。人类和动物研究均揭示了子宫血管阻力增加和子宫血流量降低在先兆子痫和 IUGR 中的致病作用。我们最近的研究表明，高原缺氧会抑制妊娠引起的子宫动脉适应，并增加妊娠羊的子宫血管阻力和全身血压。在高海拔地区出生的婴儿患持续性肺动脉高压的风险显着增加。我们证明，高海拔妊娠期缺氧会升高肺血管阻力，增加肺动脉压力以及新生羔羊对急性缺氧的压力反应。此外，胎儿缺氧还会对脑血管发育产生负面影响，并增加新生儿脑室内出血的风险。缺氧介导的反应在许多细胞类型中高度整合；然而，它们是组织特异性的。在许多方面，胎儿和新生儿之间以及非怀孕状态和怀孕状态之间的这些反应存在显着差异。关于母体、胎儿和新生儿血管对妊娠期长期缺氧的反应的分子机制仍然未知。拟议的研究是一个基础广泛、多学科、综合的项目，利用生理、药理学、细胞、生化和分子方法来研究母体子宫、胎儿和新生儿肺血管和脑血管对妊娠期长期缺氧反应的机制。基于我们小组超过 25 年的研究，拟议的研究将在适应高海拔（3801 m/12,470 ft）的绵羊中进行。总体假设是，妊娠期间高海拔、长期缺氧会增加微小 RNA-210 和内质网 (ER) 应激，在母体、胎儿和新生儿血管反应的编程中差异调节自发瞬时外向电流 (STOC)，影响发育可塑性和随后的疾病风险。该研究具有很强的科学前提、新颖的概念以及创新和机械的方法。它将为理解妊娠缺氧引起的母体、胎儿和新生儿血管功能障碍的基本机制提供新的见解，影响母体健康和发育可塑性。鉴于 STOC 对于调节几乎所有血管床的血管张力和血流至关重要，揭示 STOC 在血管缺氧反应编程中功能的分子和表观遗传调节将对血管生理学和病理生理学机制的全面理解产生广泛影响。