Introduction: Strong indirect evidence implicates the involvement of advanced glycation end products (AGEs) and vascular endothelial growth factor (VEGF) in the pathogenesis of diabetic retinal edema and ischemia. Preliminary Data: (l) Retinal VEGF expression is increased in early background diabetic retinopathy. (2) Exogenous VEGF produces many of the changes of diabetic retinopathy, including retinal edema and ischemia. (3) Glucose-derived AGEs increase retinal cell VEGF expression in vitro and in vivo. (4) VEGF is the primary endothelial cell mitogen induced by AGEs. (5) Retinal vascular leakage occurs early in experimental diabetic retinopathy and coincides with the increased expression of VEGF. Hypotheses: (1) VEGF is causal for the increased vascular permeability of diabetic retinopathy. (2) Endogenous AGEs increase VEGF expression in early diabetic retinopathy. (3) AGEs, through VEGF, are operative in the development of acellular capillaries, endothelial cell proliferation, pericyte death and microaneurysms. Specific Aims: (1) To demonstrate that AGE-induced increases in retinal VEGF expression are causal for the increased retinal vascular permeability of diabetes. (2) To demonstrate that the long-term dissolution of AGE crosslinks prevents retinal VEGF upregulation and many of the anatomic alterations of diabetic retinopathy. Significance: Studies aimed at understanding the mechanisms of diabetic retinal edema and ischemia, two major causes of vision loss, will provide important information that could lead to effective treatments for diabetic retinopathy.