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

Abstract

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 highglucose conditions. Retinal EC under high-glucose conditions also expressed increased levels of fibronectin, osteopontin, and ␣ v␤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 RETINAL MICROVASCULAR COMPLICATIONS and pathological neovascularization are the major causes of blindness in patients with diabetes (16,20). How these vascular dysfunctions are brought about by diabetes and what their functional consequences are in retinal functions have been the subject of numerous studies. A causal link between diabetic hyperglycemia and the development of retinal vascular complications has been established, such that tight glucose control in diabetic patients reduces the progression of the disease (64). Therefore, hyperglycemia has been implicated in the activation of numerous key mechanisms/pathways, including oxidative and nitrative stress (8, 49), advanced glycation end products (21), and aldose reductase (10, 60), which, in concert, contribute to retinal vascular dysfunctions and diabetic retinopathies. Understanding how these pathways are activated and/or impact retinal vascular cell function under hyperglycemic conditions will aid in the development of new modalities to halt the development and progression of the disease.The effects of high-glucose concentration on proliferation and survival of various types of endothelial cells (EC), including human umbilical vein EC (HUVEC) (48, 66), human pulmonary artery EC (45), human dermal microvascular EC (34), aortic EC (22), and retinal EC (42, 55), have been previously demonstrated. However, the report of conflicting results in EC properties under high glucose (25,26,59), perhaps through different intracellular signaling pathways, makes the interpretation of these results difficult. These conflicting reports may also be explained, at least in part, by the differences in species, tissues of origin, macro-vs. microvascular EC, or experimental conditions util...

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14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

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