Genetic Regulation of Hypoxia-Induced IUGR

高海拔地区氧气供应减少限制了胎儿生长，增加了先兆子痫的发生率， 使高海拔居民成为这些并发症的风险最大的单一群体。我们已经证明了 这种与海拔高度相关的增加部分是由于母体血管反应性、生长和发育的改变 减少子宫动脉(UA)血流的重塑。此外，我们的数据表明， 与短期居住的高海拔居民相比，多代人的高海拔居民不会受到 由于UA血流量增加，IUGR随海拔升高而增加。根据最近的证据 低氧诱导转录因子(HIF)在调控中的核心作用 O2敏感基因，与妊娠障碍有关，我们的初步数据表明，它们是 在长期和短期人群中进行不同的调节，我们建议检验总体假设 HIF靶向或调控通路中的基因变异保护多代高海拔居民 来自低氧相关的IUGR。建议在怀孕期间和产后进行一系列研究 100名高海拔居民(3600米)和100名低海拔居民(300米)。女性将平均从 在高海拔地区居住多代(安第斯人)和短期(欧洲人)的人群。 具体目的是测试1)安第斯山脉血统与欧洲血统相比，是否对低氧诱导具有保护作用 IUGR因遗传因素影响HIF靶向分泌基因产物和UA血流量，2) UA血流量和胎儿生长的差异是由于HIF靶向和调节基因所致，以及3) 安第斯-欧洲在孕妇对怀孕和胎儿生长的生理反应方面的差异是 HIF靶向或调节基因影响UA血管收缩、血管扩张或 成长。这些目标得到了初步数据的支持，这些数据表明了对缺氧相关疾病的保护 与欧洲高海拔居民相比，安第斯与欧洲高海拔居民的IUGR合并UA血流量更大，更低 内皮素-1水平(EDN1)和EDN1中或附近的独特遗传变异的存在以及 其他针对缺氧诱导因子的基因。因此，我们设计了一种新的策略来耦合基因组方法 使用更传统的生理工具来识别影响母体血管反应的基因 妊娠和缺氧所致的IUGR。拟议的研究不仅与1.4亿人有关 世界各地的高海拔居民，包括科罗拉多州的10万多人，也是人数较多的 妊娠合并子宫胎盘缺血和/或胎儿缺氧的妇女。

Reduced 02 availability at high altitude restricts fetal growth and increases the frequency of preeclampsia, making high-altitude residents the single largest group at risk for these complications. We have shown that this altitude-related increase is due, in part, to alterations in maternal vascular reactivity, growth and remodeling that lessen uterine artery (UA) blood flow. Moreover our data demonstrate that multigenerational compared with shorter-term high-altitude residents are protected from the altitude-associated increase in IUGR due to greater UA blood flow. Based on recent evidence demonstrating that hypoxia-inducible transcription factors (HIFs) play a central role in regulating O2-sensitive genes, are implicated in pregnancy disorders, and our preliminary data that they are differentially regulated in long- vs. short-term populations, we propose to test the overall hypothesis that genetic variants in HIF-targeted or regulatory pathways protect multigenerational high-altitude residents from hypoxia-associated IUGR. Serial studies are proposed during pregnancy and again postpartum in 100 high- (3600 m) and 100 low- (300 m) altitude residents. Women will be drawn evenly from populations with multigenerational (Andean) vs. shorter-term (European) residence at high altitude. Specific aims are to test whether 1) Andean vs. European ancestry is protective against hypoxia-induced IUGR due genetic factors influencing HIF-targeted secretory gene products and UA blood flow, 2) differences in UA blood flow and fetal growth are due to HIF-targeted and -regulatory genes, and 3) Andean-European differences in maternal physiologic responses to pregnancy and fetal growth are the result of actions of HIF-targeted or regulatory genes influencing UA vasoconstriction, vasodilation, or growth. These aims are supported by preliminary data demonstrating protection from hypoxia-associated IUGR in Andean vs. European high-altitude residents together with greater UA blood flow, lower endothelin-1 levels (EDN1) and the presence of distinctive genetic variants in or near the EDN1 as well as other, HIF-targeted genes. Thus we have designed a novel strategy for coupling genomic approaches with more traditional physiological tools to identify genes influencing maternal vascular response to pregnancy and hypoxia-induced IUGR. The proposed studies are relevant not only for the 140 million high-altitude residents worldwide, including more than 100,000 in Colorado, but also the larger number of women whose pregnancies are complicated by uteroplacental ischemia and/or fetal hypoxia.