The overall hypothesis is that caveolin-1 (cav-1) interacts with vascular endothelial growth factor (VEGF) receptors (VEGFR) directly and/or indirectly to concentrate VEGFR initiated signaling events, i.e., Ras-Raf-MEK1-ERK2/1 and PI3K/Akt signaling modules, in the caveolae of endothelial cells (EC), thereby modulating VEGF regulation of EC proliferation, migration, and differentiation. Moreover, cav-1/caveolae may regulate placental angiogenesis by modifying the bioavailability of nitric oxide (NO) in EC. To address this hypothesis, an ovine fetoplacental artery EC model and a human placental capillary endothelial cell line will be used.
Specific Aim 1 : To further clarify if VEGFRs (i.e., KDR, Flt-1, and NP-1) are physically associated with cav-1 in vitro and in vivo, thus localized in the caveolae, and if overexpression of exogenous cav-1 or targeted down-regulation of endogenous cav-1 regulates ligand-dependent VEGFR activation.
Specific Aim 2 : To determine if targeted down-regulation of endogenous cav-1 or overexpression of exogenous cav-1 alters VEGF stimulation of cell cycle entry, proliferation, migration and differentiation.
Specific Aim 3 : To determine if VEGF activates the Ras/Raf/ERK2/1 and PI3K/Akt signaling modules in the caveolae.
Specific Aim 4 : To delineate if down-regulation of cav-1 or cav-1 overexpression modulates VEGF stimulation of MAPK and PI3K/Akt signaling pathways and the role of these pathways in VEGF-induced cell cycle entry, cell proliferation, migration, and differentiation.
Specific Aim 5 : To determine if targeted down-regulation of endogenous cav-1 or overexpresison of exogenous cav-1 alters eNOS activity thereby altering the bioavaibility Iof NO, which in turn regulates placental angiogenesis. These studies will have a great impact on our understanding of caveoli, VEGF/VEGFR, endothelial, and angiogenesis biology, all are biologically important fields we have integrated in the proposal clinically relevant to placental angiogenesis and vasodilatation for the first time. The ultimate clinical importance of this research is evident when one considers that uteroplacental endothelial adaptations to pregnancy, especially the rises in fetoplacental and uteroplacental perfusion, are linked directly to fetal growth and survivability and that these mechanisms are dysfunctional in pathologic pregnancies such as preeclampsia and IUGR.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL074947-05
Application #
7645914
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-07-01
Project End
2010-05-31
Budget Start
2008-09-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$250,000
Indirect Cost
Name
University of California Irvine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Zhang, Hong-hai; Lechuga, Thomas J; Tith, Tevy et al. (2015) S-nitrosylation of cofilin-1 mediates estradiol-17?-stimulated endothelial cytoskeleton remodeling. Mol Endocrinol 29:434-44
Zhang, Hong-Hai; Wang, Wen; Feng, Lin et al. (2015) S-nitrosylation of Cofilin-1 Serves as a Novel Pathway for VEGF-Stimulated Endothelial Cell Migration. J Cell Physiol 230:406-17
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
Chen, Dong-Bao; Zheng, Jing (2014) Regulation of placental angiogenesis. Microcirculation 21:15-25
Jiang, Yi-Zhou; Wang, Kai; Li, Yan et al. (2013) Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen. Biol Reprod 88:114
Jiang, Yi-Zhou; Wang, Kai; Li, Yan et al. (2013) Enhanced cellular responses and distinct gene profiles in human fetoplacental artery endothelial cells under chronic low oxygen. Biol Reprod 89:133
Liao, Wu-Xiang; Laurent, Louise C; Agent, Sally et al. (2012) Human placental expression of SLIT/ROBO signaling cues: effects of preeclampsia and hypoxia. Biol Reprod 86:111
Wang, Wen; Feng, Lin; Zhang, Honghai et al. (2012) Preeclampsia up-regulates angiogenesis-associated microRNA (i.e., miR-17, -20a, and -20b) that target ephrin-B2 and EPHB4 in human placenta. J Clin Endocrinol Metab 97:E1051-9
Feng, Lin; Zhang, Hong-hai; Wang, Wen et al. (2012) Compartmentalizing proximal FGFR1 signaling in ovine placental artery endothelial cell caveolae. Biol Reprod 87:40
Feng, Lin; Liao, Wu-Xiang; Luo, Quan et al. (2012) Caveolin-1 orchestrates fibroblast growth factor 2 signaling control of angiogenesis in placental artery endothelial cell caveolae. J Cell Physiol 227:2480-91

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