Although a significant body of evidence indicates a role for the retinal pigment epithelium in the development and maintenance of the choroidal vasculature, the mechanisms that underlie this relationship are unknown. In addition to an important function in the normal retina, the interactions between RPE and the choroidal vasculature are central to a number of retinal pathologies, including age-related macular diseases (ARMD) such as geographic atrophy. Several findings point to a possible role for vascular endothelial growth factor (VEGF) as a mediator of the RPE cell survival effect on choroidai vessels. Data from experimental models indicate a survival function for VEGF in vessel stabilization, RPE in the adult make VEGF, and choroidal endothelial cells express VEGF receptors, which we show are constitutively activated in the adult. We therefore propose to test the hypothesis that RPE-derived VEGF is necessary for the development and maintenance of the choroidal vasculature by the following aims. (1) To determine the expression pattern of VEGF family members and their receptors (VEGFR1, VEGFR2, VEGFR3, and the neuropilins), and VEGF receptor activation status in the choroid-RPE complex during development and in the adult. (2) To examine the role of VEGF in choroidal vascular development using mice that express only VEGF188, an isoform not normally made by RPE, and mice with an RPE-specific deletion of VEGF. The role of VEGF in the maintenance of the adult choroidal vasculature will be determined by inhibition of the VEGFR2 tyrosine phosphorylation using SU5416, a small molecule VEGFR2-selective tyrosine kinase inhibitor; and interference with the interaction between RPE-derived VEGF and choroidal endothelial VEGFR2 using an inducible DN-VEGFR2 transgenic mouse model. (3) To assess the ability of exogenously added VEGF to """"""""rescue"""""""" choroidal loss due to experimentally induced RPE destruction. RPE will be destroyed by systemic administration of sodium iodate (NalO3) and the role of VEGF in trophic effects of RPE on the choroid will be assessed by investigating the ability of exogenously added VEGF to rescue the choroidal loss. Results of these studies will provide mechanistic insight into the means by which RPE support normal choroidal function, and thus may reveal targets for therapeutic intervention into the blinding diseases of macular degeneration.
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