Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes

Abstract

OBJECTIVE - Increased vascular permeability due to alteration of the blood-retinal barrier (BRB) is one of the major complications in early diabetes. The aim of the present study was to determine whether diabetes alters the cellular expression and distribution of the adherens junction protein vascular endothelial (VE)-cadherin in retinal endothelial cells and if this alteration is mediated by proteinase activity. RESEARCH DESIGN AND METHODS - Diabetes was induced in Brown Norway rats using streptozotocin, and retinal vascular permeability was measured by the Evans blue technique. The expression of matrix metalloproteinases (MMPs) and VE-cadherin was examined in isolated retinal vessels or cultured endothelial cells in response to diabetes and advanced glycation end products (AGEs). The cleavage of VE-cadherin from the endothelial cell surface was monitored by Western blotting following MMP or AGE treatment. RESULTS - Retinal vascular permeability was significantly increased in rats following 2 weeks of diabetes coincident with a decrease of VE-cadherin expression. This increased vascular permeability could be inhibited with an MMP inhibitor. Treatment of endothelial cells with AGE-BSA led to a reduction of VE-cadherin staining on the cell surface and increased permeability, which was MMP mediated. Treatment of cells with specific MMPs or AGEs resulted in cleavage of VE-cadherin from the cell surface. CONCLUSIONS - These observations suggest a possible mechanism by which diabetes contributes to BRB breakdown through proteolytic degradation of VE-cadherin. This may indicate a role for extracellular proteinases in alteration of the BRB seen in diabetic retinopathy. © 2007 by the American Diabetes Association.