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.
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.
|Boeldt, Derek S; Hankes, Amanda C; Alvarez, Roxanne E et al. (2014) Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Adv Exp Med Biol 814:27-47|
|Zhao, Ying-Jie; Zou, Qing-Yun; Li, Yan et al. (2014) Expression of G-protein subunit ?-14 is increased in human placentas from preeclamptic pregnancies. J Histochem Cytochem 62:347-54|
|Jiang, Yi-Zhou; Li, Yan; Wang, Kai et al. (2014) Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen. Mol Cell Endocrinol 391:60-7|
|Li, Hui-Hui; Zhao, Ying-Jie; Li, Yan et al. (2014) Estradiol 17? and its metabolites stimulate cell proliferation and antagonize ascorbic acid-suppressed cell proliferation in human ovarian cancer cells. Reprod Sci 21:102-11|
|Chen, Dong-Bao; Zheng, Jing (2014) Regulation of placental angiogenesis. Microcirculation 21:15-25|
|Ampey, Bryan C; Morschauser, Timothy J; Lampe, Paul D et al. (2014) Gap junction regulation of vascular tone: implications of modulatory intercellular communication during gestation. Adv Exp Med Biol 814:117-32|
|Boeldt, Derek S; Grummer, Mary A; Magness, Ronald R et al. (2014) Altered VEGF-stimulated Ca2+ signaling in part underlies pregnancy-adapted eNOS activity in UAEC. J Endocrinol 223:1-11|
|Schreier, David A; Hacker, Timothy A; Hunter, Kendall et al. (2014) Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol (1985) 117:833-9|
|Morschauser, Timothy J; Ramadoss, Jayanth; Koch, Jill M et al. (2014) Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis. Hypertension 63:589-94|
|Giakoumopoulos, M; Golos, T G (2013) Embryonic stem cell-derived trophoblast differentiation: a comparative review of the biology, function, and signaling mechanisms. J Endocrinol 216:R33-45|
Showing the most recent 10 out of 53 publications