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

这项多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、长期缺氧反应的基本细胞和分子机制。缺氧是机体内平衡机制最常见和最严重的应激因素之一，妊娠期缺氧对母体健康和发育可塑性有深远的不利影响。妊娠期缺氧与临床并发症的高发相关，包括先兆子痫和胎儿宫内生长受限（IUGR）。人类和动物研究都揭示了子宫血管阻力增加和子宫血流量降低在子痫前期和IUGR中的致病作用。我们最近的研究表明，高原缺氧抑制妊娠绵羊子宫动脉适应性，增加子宫血管阻力和全身血压。在高海拔地区出生的婴儿出现持续性肺动脉高压的风险明显增加。我们证明了妊娠期高海拔缺氧会增加新生羔羊的肺血管阻力，增加肺动脉压力和对急性缺氧的压力反应。此外，胎儿缺氧对脑血管发育有负面影响，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；尽管如此，它们是组织特异性的。在许多方面，这些反应在胎儿和新生儿之间，以及在未怀孕和怀孕状态之间存在显著差异。母体、胎儿和新生儿对妊娠期长期缺氧的血管反应的分子机制尚不清楚。本研究是一项基础广泛、多学科、综合的研究项目，采用生理、药理学、细胞、生化和分子等方法，探讨母体子宫、胎儿和新生儿肺部和脑血管对妊娠期长期缺氧的反应机制。根据我们小组近25年的研究，这项拟议的研究将在适应高海拔（3801米/ 12470英尺）的绵羊中进行。总体假设是，妊娠期高海拔、长期缺氧增加了微RNA-210和内质网（ER）应激，差异调节了母体、胎儿和新生儿血管反应编程中的自发瞬态外向电流（STOCs），影响发育可塑性和随后的疾病风险。本研究具有较强的科学前提，概念新颖，方法新颖，具有一定的科学性。这将为理解由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、影响母体健康和发育可塑性提供新的见解。鉴于STOCs在调节几乎所有血管床的血管张力和血流方面具有重要意义，揭示STOCs在规划血管缺氧反应中的分子和表观遗传学调控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。

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.