ROLE OF 4 INTEGRIN (CD49d) IN THE PATHOGENESIS OF DIABETIC RETINOPATHY

¹ Retinal Angiogenesis Research Laboratory, MEEI, Boston, Massachusetts, United States
² Retinal Angiogenesis Research Laboratory, MEEI, 325 Cambridge Street, 3rd Floor, Boston, Massachusetts, 2114, United States
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States

^* To whom correspondence should be addressed. E-mail: poulakiv{at}gmail.com.

	Abstract

Purpose: The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin 4 (CD49d), in complex with integrin 1, forms Very Late Antigen-4 (VLA-4), that interacts with vascular cell adhesion molecule-1 (VCAM-1). We have now studied the role of integrin 4/CD49d in the pathogenesis of diabetic retinopathy. Methods: Diabetes mellitus was induced in Long Evans rats with streptozotocin and an anti-4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF- levels, and NF-B activity were measured by ELISA. Results: Blockade of 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-B activation, VEGF and TNF- protein levels, and also reduced significantly the diabetes-induced leukocyte adhesion and vascular leakage. Conclusions: Our data identify 4 integrin/CD49d as a mediator of leukocyte adhesion and the resulting early signature pathologies of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in diabetic patients.

Key Words: diabetic retinopathy, VLA-4, VCAM-1, CD49d, blood-retinal barrier breakdown

This article has been cited by other articles:

				A. Stahl, K. M. Connor, P. Sapieha, J. Chen, R. J. Dennison, N. M. Krah, M. R. Seaward, K. L. Willett, C. M. Aderman, K. I. Guerin, et al. The Mouse Retina as an Angiogenesis Model Invest. Ophthalmol. Vis. Sci., June 1, 2010; 51(6): 2813 - 2826. [Abstract] [Full Text] [PDF]