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孕产妇，胎儿和新生儿血管适应的基本细胞和分子机制，以响应高海拔，妊娠期间长期缺氧。缺氧是生物体稳态机制最常见和最严重的压力之一，妊娠期间缺氧对孕产妇的健康和发育可塑性产生深远的不利影响。妊娠缺氧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（IUGR）。人类和动物研究都表明，子宫血管抵抗增加并降低子宫血流的病因作用。我们最近的研究表明，高海拔缺氧抑制了妊娠引起的子宫动脉适应，并增加了子宫血管抵抗和孕妇的全身血压。在高海拔地区出生的婴儿显示出持续性肺动脉高压的风险显着增加。我们证明，高海拔高度升高的妊娠缺氧肺血管耐药性，肺动脉压力增加以及对新生羔羊急性缺氧的压力反应。此外，胎儿缺氧对脑血管发育产生负面影响，并增加了新生儿脑室内出血的风险。低氧介导的反应在许多细胞类型中高度整合。尽管如此，它们是特定于组织的。在许多方面，胎儿和新生儿以及非妊娠和怀孕状态之间的这些反应显着差异。孕产妇，胎儿和新生血管反应对妊娠长期缺氧的基础编程的分子机制仍然未知。拟议的研究是基于生理，药理，细胞，生化和分子方法的广泛基于多学科的，综合的项目，用于研究孕产妇子宫的基础机制，以及胎儿和新生的肺和新生的肺血管对妊娠中长期缺氧的脑血管反应。根据我们小组的25年研究，拟议的研究将以适应高海拔的绵羊进行（3801 m/12,470英尺）。总体假设是，高海拔，妊娠期间的长期缺氧会增加微RNA-210和内质网应激（ER）应力，从而在孕产妇，胎儿和新生血管反应的编程中差异调节自发性短暂性外电流（STOC），从而影响发育量的发育可塑性以及对疾病的影响。拟议的研究具有强大的科学前提，具有新颖的概念以及一种创新和机械的方法。它将为对孕产妇，胎儿和新生血管功能障碍的基本机制的理解提供新的见解，从而影响孕产妇的健康和发育可塑性。鉴于STOC在几乎所有血管床的血管张力和血流中至关重要，这揭示了STOCS对缺氧的血管反应编程中的分子和表观遗传调节功能，将对血管生理学和病理生理学中的机制的全面理解产生广泛的影响。