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Neovascular diseases of the retina are a major cause of blindness worldwide. Hypoxia is thought to be a common precursor to neovascularization in many retinal diseases, but the factors involved in the hypoxic neovascular response have not been fully identified. To Retinal neovascularization is a major cause of blindness in the United States (1). Pathologic retinal angiogenesis is a final common pathway leading to vision loss in diseases such as retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration (2-4). Despite the prevalence of these diseases, the biochemical events responsible for retinal neovascularization are not fully understood. It is hoped that a better understanding of the fundamental basis of retinal neovascularization will improve treatment and prevention of retinal vascular diseases.In these eye diseases, as in tumor growth and wound healing, hypoxia appears to be a common precursor to neovascularization (5, 6). In the 1940s and 1950s, Michaelson (7) and Ashton et al. (8) postulated that retinal neovascularization was caused by release of a "vasoformative factor" from the retina in response to hypoxia. Since these initial hypotheses, it has become widely accepted that retinal hypoxia results in the release of factors that influence new blood vessel growth (3). The angiogenic factors responsible for retinal neovascularization, however, have not been conclusively identified.Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that was identified and cloned by several groups of investigators (9-12). The expression of VEGF/VPF is stimulated by hypoxia, and VEGF/VPF has been demonstrated to be required for tumor-associated angiogenesis (13)(14)(15) (17)(18)(19)(20). VEGF/VPF levels also increase in a primate model of iris neovascularization (21). However, the location and time course of VEGF/VPF expression in association with retinal neovascularization has not been delineated nor has it been determined if VEGF/VPF has a direct role in the induction of retinal neovascularization.The goal of the present study was to examine the role of VEGF/VPF in retinal neovascularization by studying the time course and location of VEGF/VPF expression in a mouse model of proliferative retinopathy (22). In this model, mice are exposed to hyperoxia, resulting in obliteration of the posterior retinal vessels. The mice are then returned to room air, which is presumed to cause relative hypoxia of the now nonperfused retina, producing a quantifiable neovascular response in 100% of animals. Using this model, the expression of VEGF/VPF mRNA and protein were studied by RNA (Northern) blot analysis, in situ hybridization, and immunohistochemical confocal microscopy. These data demonstrate the role of VEGF/ VPF in an animal model of retinal neovascularization, which has not previously been done to our knowledge.EXPERIMENTAL PROCEDURES Mouse Model. The study adhered to the "Association for Research in Vision and Ophthalmolog...

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Excessive retinal vascular permeability contributes to the pathogenesis of proliferative diabetic retinopathy and diabetic macular edema, leading causes of vision loss in working-age adults. Using mass spectroscopy-based proteomics, we detected 117 proteins in human vitreous and elevated levels of extracellular carbonic anhydrase-I (CA-I) in vitreous from individuals with diabetic retinopathy, suggesting that retinal hemorrhage and erythrocyte lysis contribute to the diabetic vitreous proteome. Intravitreous injection of CA-I in rats increased retinal vessel leakage and caused intraretinal edema. CA-I-induced alkalinization of vitreous increased kallikrein activity and its generation of factor XIIa, revealing a new pathway for contact system activation. CA-I-induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein and bradykinin receptor antagonism. Subdural infusion of CA-I in rats induced cerebral vascular permeability, suggesting that extracellular CA-I could have broad relevance to neurovascular edema. Inhibition of extracellular CA-I and kallikrein-mediated innate inflammation could provide new therapeutic opportunities for the treatment of hemorrhage-induced retinal and cerebral edema.