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.

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Normal fetal vascular growth and function are critical for fetal growth. G-protein subunits GNA11 and 14 have been implicated in mediating vascular growth and hypertension;however, little is known about their actions in endothelial cells. Thus, the goal of this application is to examine physiological roles of GNA14 and GNA11 in fetal endothelia, which will provide additional novel signaling therapeutic targets.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Wisconsin Madison
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