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Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes

¹ Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
² Division of Ophthalmology, Department of Surgery,University of New Mexico School of Medicine, Albuquerque, NM 87131
³ New Mexico VA Health Care System, Albuquerque, NM 87131

Correspondence: adas{at}unm.edu

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 if diabetes alters the cellular expression and distribution of the adherens junction protein 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 AGE (advanced glycation end-products). 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 AGE 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.

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