Roles of GNA14 and GNA11 in Human Fetal Endothelial Cells

在怀孕期间，胎儿和胎盘血管的急剧生长是胎儿和胎盘血流量显著增加以支持发育中的胎儿所必需的。在这些过程中，血管内皮细胞处于生理性慢性缺氧（pCH）下，这对于细胞稳态是至关重要的，因为已知更严重的缺氧与许多内皮功能障碍相关的疾病如高血压和先兆子痫相关。VEGF和FGF 2是两种有效的生长因子，通过蛋白激酶以及G蛋白（包括GNA 11和GNA 14）积极调节许多内皮功能。具体而言，GNA 11已被证明是VEGF模拟的新血管生长所必需的。GNA 14还 与人类高血压和先兆子痫有关然而，关于GNA 14在内皮细胞中的作用还一无所知。为了研究GNA 14和GNA 11在介导胎儿内皮功能中的作用和潜在的信号传导机制，我们建议使用在pCH下建立的原代HUVE和HUAE细胞系来检测GNA 14和GNA 11在调节pCH增强的血管生长和响应VEGF和FGF 2的血管舒张作用中的作用。（~ 20 - 25天; 37 ℃，5%CO2，3%O2）和标准细胞培养常氧（~ 20 - 25天; 37 ℃，5%CO2，95%空气，SCCN）。这些研究首次系统地探索了GNA 14在介导内皮功能中的作用，以及GNA 11在介导eNOS表达和激活中的作用。这些研究结果将极大地促进我们对GNA 14和GNA 11在人胎儿血管生成和内皮血管舒张中作用的理解。 功能，特别是在pCH下，这将为这些高血压相关疾病的治疗干预提供新靶点的线索。

During pregnancy, dramatic growth of fetal and placental vasculatures is required for remarkable increases in fetal and placental blood flows to supporting the developing fetus. During these processes, vascular endothelial cells reside under physiological chronic hypoxia (pCH), which is critical for cell homeostasis as more severe hypoxia is known to be associated with many endothelial dysfunction related diseases such hypertension and preeclampsia. VEGF and FGF2, two potent growth factors actively regulate many endothelial functions via protein kinases and also via G proteins including GNA11 and GNA14. Specifically, GNA11 has been shown to be required for VEGF-simulated growth of new blood vessels. GNA14 has also been implicated in human hypertension and preeclampsia. However, nothing is known regarding the actions of GNA14 in endothelial cells. To study the roles and underlying signaling mechanisms of GNA14 and GNA11 in mediating fetal endothelial functions, we propose to examine the roles of GNA14 and GNA11 in modulating pCH-enhanced vascular growth and vasodilatory actions in response to VEGF and FGF2 using primary HUVE and HUAE cell lines established under pCH (-20-25 days; 37 C, 5% C02, 3% 02) and standard cell culture normoxia (-20-25 days; 37 C, 5% C02, 95% air, SCCN). These studies are the first to systemically explore the role of GNA14 in mediating endothelial functions, and the role of GNA11 in mediating eNOS expression and activation. The findings of these studies will greatly advance our understanding of actions of GNA14 and GNA11 in human fetal angiogenic and endothelial vasodilatory functions, particularity under pCH, which will provide clues about novel targets for therapeutic intervention in these hypertension-related diseases.