Ocular neovascularization is the most common pathological change observed in the vast majority of eye diseases that result in catastrophic loss of vision. For example, the two leading causes of blindness in the United States, diabetic retinopathy and macular degeneration, are characterized by the growth of new blood vessels from pre-existing retinal and choroidal vessels, respectively. Over the past decade, a number of angiogenic substances have been identified in eyes from human patients and animal models with angiogenic eye disease. A final common pathway in the angiogenic process is the proliferation and migration of normally quiescent vascular endothelial cells. An important part of this process is the selective display of adhesion molecules on the proliferating endothelial cell surface. One class of adhesion receptors, called integrins, are displayed as heterodimers consisting of an alpha and beta subunit. The integrin alpha v beta 3 allows endothelial cells to interact with a wide variety of extracellular matrix components and appears to be a marker of newly formed blood vessels. A conformation-dependent antibody to, and peptide antagonists of, this integrin specifically inhibit angiogenesis in several in vitro systems. Our broad, long-term goals are to examine the role of integrins, in particular the integrin alpha v beta 3, during ocular angiogenesis. Once we have examined the relationship between these integrins and the growth of new blood vessels in the eye, we will test the efficacy of antagonists to these integrins in the inhibition of ocular neovascularization.
Our specific aims are to: (1) examine the relationship between alpha v beta 3, integrin and angiogenesis in a fibroblast growth factor-stimulated corneal pocket model; (2) examine the distribution of alpha v beta 3 integrin in human neovascular eye disease; (3) examine the relationship between alpha v beta 3 integrin and angiogenesis in a model for iris neovascularization; and (4) investigate the role of integrin alpha v beta 3 in ocular angiogenesis stimulated by multiple cytokines and fragments of human ocular melanoma. The use of integrin antagonists represents a potentially powerful therapeutic; the mechanism of action is well characterized, it appears to be highly specific with no detectable effect on mature blood vessels, and, most importantly, appears to interfere with angiogenesis at a final common pathway in the neovascular process regardless of the stimulus. Such an approach will provide a rational basis for the development of therapeutics useful in inhibiting ocular angiogenesis.
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