High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs

Departments of 1 Ophthalmology and Visual Sciences, and 2 Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Submitted 18 June 2008 ; accepted in final form 16 October 2008 Hyperglycemia impacts retinal vascular function and promotes the development and progression of diabetic retinopathy, which ultimately results in growth of new blood vessels and loss of vision. How high glucose affects retinal endothelial cell (EC) properties requires further investigation. Here we determined the impact of high glucose on mouse retinal EC function in vitro. High glucose significantly enhanced the migration of retinal EC without impacting their proliferation, apoptosis, adhesion, and capillary morphogenesis. The enhanced migration of retinal EC under high glucose was reversed in the presence of the antioxidant N -acetylcysteine, suggesting increased oxidative stress under high-glucose conditions. Retinal EC under high-glucose conditions also expressed increased levels of fibronectin, osteopontin, and v β 3 -integrin, and reduced levels of thrombospondin-1. These changes were concomitant with sustained activation of the downstream prosurvival and promigratory signaling pathways, including Src kinase, phosphatidylinositol 3-kinase/Akt1/endothelial nitric oxide synthase, and ERKs. The sustained activation of these signaling pathways was essential for enhanced migration of retinal EC under high-glucose conditions. Together, our results indicate the exposure of retinal EC to high glucose promotes a promigratory phenotype. Thus alterations in the proangiogenic properties of retinal EC during diabetes may contribute to the development and pathogenesis of diabetic retinopathy. diabetic retinopathy; angiogenesis; integrins; extracellular matrix; thrombospondin; osteopontin Address for reprint requests and other correspondence: N. Sheibani, Dept. of Ophthalmology and Visual Sciences, Univ. of Wisconsin, 600 Highland Ave., K6/458 CSC, Madison, WI 53792-4673 (e-mail: nsheibanikar{at}wisc.edu )