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

该多PI应用的总体目标是了解妊娠期间母体、胎儿和新生儿血管适应高海拔、长期缺氧的基本细胞和分子机制。缺氧是生物体内平衡机制最常见和最严重的应激之一，妊娠期缺氧对母体健康和发育可塑性有深远的不利影响。胎儿缺氧与临床并发症的高发生率相关，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先兆子痫和IUGR中的致病作用。我们最近的研究表明，高原低氧抑制妊娠诱导的子宫动脉适应性，增加子宫血管阻力和全身血压。出生在高海拔地区的婴儿患持续性肺动脉高压的风险显著增加。我们证明，在高原妊娠缺氧升高肺血管阻力和增加肺动脉压力和压力反应急性缺氧新生羔羊。此外，胎儿缺氧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;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非妊娠和妊娠状态之间存在显著差异。妊娠期母体、胎儿和新生儿血管对长期缺氧反应的分子机制尚不清楚。该研究是一项基础广泛的多学科综合研究，采用生理学、药理学、细胞学、生物化学和分子学方法，研究妊娠期长期缺氧对母体子宫、胎儿和新生儿肺血管和脑血管反应的机制。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米/12，470英尺）的绵羊中进行。总体假设是，妊娠期间的高海拔、长期缺氧增加了microRNA-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。该研究具有较强的科学性，概念新颖，方法创新，方法机械。它将为理解妊娠缺氧引起的孕产妇，胎儿和新生儿血管功能障碍的基本机制提供新的见解，影响孕产妇健康和发育可塑性。鉴于STOC在调节几乎所有血管床的血管张力和血流方面具有根本性的重要性，揭示STOC在血管对缺氧反应的编程中的功能的分子和表观遗传调节将对全面理解血管生理学和病理生理学机制产生广泛影响。

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.