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Eirini Iliaki, Vassiliki Poulaki, Nicholas Mitsiades, Constantine S. Mitsiades, Joan W. Miller, Evangelos S. Gragoudas; Role of α4 Integrin (CD49d) in the Pathogenesis of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(10):4898-4904. doi: 10.1167/iovs.08-2013.
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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 α4 (CD49d), in complex with integrin β1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin α4/CD49d in the pathogenesis of diabetic retinopathy.
methods. Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-α4 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-α levels and NF-κB activity were measured by ELISA.
results. Blockade of α4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-κB activation, VEGF, and TNF-α protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage.
conclusions. These data identify α4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.
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