Inflammatory cytokine-specific alterations in retinal endothelial cell function

Diabetic retinopathy (DR) is recognized as a chronic low-grade inflammatory disease. Retinal microvascular cell dysfunction and loss play an important role in the pathogenesis of DR. However, the basic mechanisms underlying the development and progression of DR are poorly understood. Many recent studies indicate that increased production of inflammatory factors either systemically and/or locally, is strongly associated with vascular dysfunction during diabetes. Here we sought to determine the specific impact of different inflammatory mediators on retinal endothelial cell (EC) function. Inflammatory mediators TNF-α and IL-1β attenuated the migration and capillary morphogenesis of retinal EC. These dysfunctions were associated with an increased production of reactive oxygen species, expression of inducible nitric oxide synthase, and production of total nitrate/nitrite. Incubation of retinal EC with TNF-α and IL-1β altered VE-cadherin localization, as well as the expression of other junctional proteins. In addition, TNF-α and IL-1β also altered the production of various ECM proteins including osteopontin, collagen IV, and tenascin-C. Mechanistically, these changes were concomitant with the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. In contrast, incubation of retinal EC with MCP-1 minimally affected their migratory, junctional, and ECM properties. Together our results indicate that the presence of inflammatory mediators in diabetes may have specific and significant impact on vascular cell function, and contribute to the pathogenesis of DR.