Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated levels of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. To understand the functional significance of inflammation and inflammatory mediators in retinal neovascularization, we performed preliminary studies using mouse model of oxygen-induced retinopathy. Our preliminary studies suggest a predominant role caspase-3 and inflammatory caspase (caspase-1) in retinal neovascularization. Our primary hypothesis to be tested is novel and fills some voids in our understanding about pathological neoangiogenesis. The specific aims of our proposed studies are to test the hypotheses that (1) IL-33 and caspases mediates hypoxia-induced pathological retinal neovascularization, (2) IL-33/ST2L mediated ADAMTS10 or VE-cadherin activation regulates sprouting angiogenesis and vessel branching, and (3) IL-33/ST2L signaling regulates the functional polarization of inflammatory cells to M2-like macrophages in hypoxic retina. Achieving these specific aims will elucidate the mechanisms through which various inflammatory molecules affect retinal neovascularization and open up a new line of understanding about the pathophysiology of various proliferative retinopathies. In addition, the proposed research will certainly contribute to the development of new therapeutic strategies against proliferative diabetic retinopathy and retinopathy of prematurity.