Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy

Abstract

Recent studies on the pathogenesis of diabetic retinopathy have focused on correcting adverse biochemical alterations, but there have been fewer efforts to enhance prosurvival pathways. Bcl-2 is the archetypal member of a group of antiapoptotic proteins. In this study, we investigated the ability of overexpressing Bcl-2 in vascular endothelium to protect against early stages of diabetic retinopathy. Transgenic mice overexpressing Bcl-2 regulated by the pre-proendothelin promoter were generated, resulting in increased endothelial Bcl-2. Diabetes was induced with streptozotocin, and mice were sacrificed at 2 months of study to measure superoxide generation, leukostasis, and immunohistochemistry, and at 7 months to assess retinal histopathology. Diabetes of 2 months duration caused a significant decrease in expression of Bcl-2 in retina, upregulation of Bax in whole retina and isolated retinal microvessels, and increased generation of retinal superoxide and leukostasis. Seven months of diabetes caused a significant increase in the number of degenerate (acellular) capillaries in diabetic animals. Furthermore, overexpression of Bcl-2 in the vascular endothelium inhibited the diabetes-induced degeneration of retinal capillaries and aberrant superoxide generation, but had no effect on Bax expression or leukostasis. Therefore, overexpression of Bcl-2 in endothelial cells inhibits the capillary degeneration that is characteristic of the early stages of diabetic retinopathy, and this effect seems likely to involve inhibition of oxidative stress.