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Nader Sheibani, Tammy L. Palenski, Christine M. Sorenson; Attenuation of the Proangiogenic Properties of Retinal Endothelial Cells by Inflammatory Cytokines. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3011.
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Diabetic retinopathy (DR) is a major complication of diabetes afflicting roughly 40% of adults with the disease, with 5-10% developing severe vision-threatening complications. The basic mechanisms underlying the pathogenesis of DR are poorly understood. Many studies have demonstrated that increased production of inflammatory mediators is strongly associated with vascular changes in DR. However, the source and targets of these inflammatory mediators remain elusive. The objective of this study was to determine the impact of inflammatory cytokines TNF-α, IL-1β and MCP-1 on retinal EC function using a variety of assays including viability, apoptosis, proliferation, migration, and capillary morphogenesis.
The expression of endothelial nitric oxide synthase and nitric oxide levels, as well as the production of various extracellular (ECM) proteins were determined. We also assessed retinal EC adhesion on various ECM proteins, their junctional organization, VEGF expression, and oxidative stress state after incubation with various inflammatory cytokines.
Cell viability and proliferation of retinal EC incubated with TNF-α, IL-1β or MCP-1 for 24 h was not affected. Incubation with TNF-α and IL-1β, but not MCP-1, decreased retinal EC migration and their ability to undergo capillary morphogenesis. Incubation with TNF-α and IL-1β, but not MCP-1, for 48 h resulted in increased production of VEGF, increased oxidative stress, and abnormal junctional localization of VE-cadherin at sites of the cell-cell contact consistent with altered cellular permeability.
Together our results demonstrate that the inflammatory cytokines have specific adverse effects on angiogenic properties of retinal EC which is associated with increased oxidative stress and altered vascular permeability. Thus, altered production of proinflammatory cytokines during diabetes has a significant impact on retinal vascular function and pathogenesis of DR.
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