The goal of this application is to test the hypothesis that the growth and survival of ocular blood vessels depends on a subset of specific vascular endothelial growth factor (VEGF) isoforms and receptors. It is well established that blood vessel growth occurs in association with hypoxia and inflammation, but the molecular mechanisms have not been elucidated. Preliminary data: (1) Corneal VEGF expression increases 10-fold in inflamed cornea and is temporally and spatially correlated with corneal neovascularization. (2) Corneal epithelium and leukocytes express VEGF in inflamed cornea in vivo. (3) Interleukin-1B and hypoxia increase corneal epithelial cell and leukocyte VEGF expression in vitro. (4) Constitutive VEGF expression varies within the eye and is correlated with the survival of new and established non-growing ocular blood vessels. (5) Ribonuclease protection assays have been developed for the quantitation of VEGF isoforms and receptors in ocular tissues. (6) Methods have been developed to investigate the biological actions of the individual VEGF isoforms and receptors in vivo.
Specific aims : (1) To provide direct evidence that short-term and long-term ocular surface blood vessel survival requires VEGF. (2) To directly define the biological actions of the individual VEGF isoforms and receptors in vivo and to localize and quantify their expression in adult eyes. (3) to determine the mechanism and requirement of VEGF induction in inflammation-associated corneal neovasclarization. Significance. These studies may directly identify (i) the first endogenous survival factor for new and established blood vessels in the adult eye; (ii) the specific VEGF isoforms and receptors which mediate its biological actions in vivo; (iii) the first functional endogenous corneal angiogenic factor; (iv) the operative in vivo mechanism(s) which induce VEGF expression in inflamed cornea.
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