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AP Adamis, V Poulaki, T Qaum, Q Xu, Y Moromizato, S-E Bursell, SJ Wiegand, J Rudge, G Yancopoulos, A Joussen; Suppression of Diabetic Retinopathy with Angiopoietin-1 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2965.
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Purpose:A critical early pathology in diabetic retinopathy is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1 (ICAM-1). Recent findings with angiopoietin-1 suggested that it might be worth evaluating in models of diabetic retinopathy. Methods: Diabetes was induced with streptozotocin in mice and rats. Angiopoietin-1 was delivered locally via intravitreous injection (rats) or systemically via an adenovirus (mice). Retinal leukostasis, blood-retinal barrier breakdown and endothelial cell injury were quantified. Retinal VEGF and ICAM-1 levels were assessed, as were retinal levels for eNOS, nitric oxide, Akt and MAP kinase activity. Retinal VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera. Results: Angiopoietin-1 prevented and reversed many of the diabetic retinal vascular changes associated with both new and established diabetes. Specifically, angiopoietin-1 normalized retinal vascular endothelial growth factor (VEGF) and ICAM-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide and Akt and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was specifically inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Conclusion: These data identify new vascular and anti-inflammatory bioactivities for angiopoietin-1. They also highlight angiopoietin-1 as the first known naturally occurring protein that directly protects the retinal vasculature in diabetes.
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