Continued studies of the pathogenesis of choroidal neovascularization (CNV) are proposed.
Specific aims directed at an analysis of the effects of retinal pigment epithelial (RPE) and macrophage-derived cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF), on CNV. We propose new studies on the role of the angiopoietins (Ang1, Ang2) in CNV and suggest a new model in which Ang1 and Ang2 act in concert with VEGF to mediate the development of CNV. Hypotheses: We suggest that Ang2 expression on choroidal endothelial cells (CECs) is a critical early step leading to choroidal angiogenesis in the presence of VEGF. Ang1 expression by RPE then promotes the survival, and maturation of these new vessels. Continued Ang1 expression after withdrawal of VEGF expression leads to vessel maturation while continued Ang2 expression leads to vascular regression. Soluble Tie2 secreted by RPE and CECs modulates the local effects of Ang1 and Ang2 on CNV formation.
Specific aims to test this model are: (1) determine the temporal and spatial expression patterns of Ang1, Ang2, and Tie2 in CNV membranes and the regulation of Ang1, Ang2 and Tie2 expression by RPE and CECs in vitro; (2) determine the mechanisms by which activation of the receptor for Ang1 (Tie2) stimulates the development, maturation and survival of CECs in vitro, and CNV in vivo; and (3) determine the mechanisms by which Ang2 and soluble Tie2 modulate Ang-induced Tie2 activity in CECs in vitro, and CNV in vivo.
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