Proliferative ocular vascular complications constitute a common pathological response associated with disorders involving significant intraocular ischemia. The subsequent exuberant vasoproliferation of the retinal microvasculature often results in irreversible vision loss. This proposal investigates the role of vascular endothelial cell growth factor (VEGF), an endothelial cell-specific angiogenic and vasopermeability factor in cultured ocular cells and in the human eye. The applicant has demonstrated high affinity VEGF receptors on retinal endothelial cells, VEGF-induced proliferation of retinal endothelial cells, reversible VEGF mRNA induction by hypoxia in several retinal cell types, and VEGF elevation in human eyes with active neovascularization. Preliminary data suggested VEGF receptor expression and retinal endothelial cells was modulated by hypoxia. This proposal will further delineate the mechanism by which VEGF and VEGF receptor expression are modulated by hypoxia and investigate the early gene expression changes induced by this receptor-ligand interaction by: (1) characterizing the response of VEGF and VEGF receptor to experimental ischemia-like conditions; (2) delineating the role of adenosine, adenosine receptors, and antioxidants on hypoxia-induced VEGF and VEGF receptor expression; and (3) locating oxygen-responsive regions in the human VEGF promoter and four isolated retinal endothelial cell genes whose expression is altered by VEGF stimulation. These investigations will help delineate the mechanisms by which hypoxia-induced VEGF expression in VEGF action occur.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29EY010827-01A1
Application #
2164971
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-09-01
Project End
2000-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
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Suzuma, Izumi; Suzuma, Kiyoshi; Ueki, Kohjiro et al. (2002) Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-zeta but not by stretch-induced ERK1/2, Akt, Ras, or classical/novel PKC pathways. J Biol Chem 277:1047-57
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Hata, Y; Duh, E; Zhang, K et al. (1998) Transcription factors Sp1 and Sp3 alter vascular endothelial growth factor receptor expression through a novel recognition sequence. J Biol Chem 273:19294-303
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