M.A. Behzadian

Vascular Endothelial Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress

Retinal neovascularization and macular edema are central features of diabetic retinopathy, a major cause of blindness in working age adults. The currently established treatment for diabetic retinopathy targets the vascular pathology by laser photocoagulation. This approach is associated with significant adverse effects due the destruction of neural tissue and is not always effective. Characterization of the molecular and cellular processes involved in vascular growth and hyperpermeability has led to the recognition that the angiogenic growth factor and vascular permeability factor VEGF (vascular endothelial growth factor) play a pivotal role in the retinal microvascular complications of diabetes. Thus, VEGF represents an important target for therapeutic intervention in diabetic retinopathy. Agents that directly inhibit the actions of VEGF and its receptors show considerable promise, but have not proven to be completely effective in blocking pathological angiogenesis. Therefore, a better understanding of the molecular events that control VEGF expression and mediate its downstream actions is important to define more precise therapeutic targets for intervention in diabetic retinopathy. This review highlights the current understanding of the process by which VEGF gene expression is regulated and how VEGFs biological effects are altered during diabetes. In particular, cellular and molecular alterations seen in diabetic models are considered in the context of high glucose-mediated oxidative stress effects on VEGF expression and action. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions in the diabetic retina are considered.

Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

Diabetes-induced breakdown of the blood-retinal barrier (BRB) has been linked to hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and is likely mediated by an increase in oxidative stress. We have shown that VEGF increases permeability of retinal endothelial cells (REC) by inducing expression of urokinase plasminogen activator receptor (uPAR). The purpose of this study was to define the role of superoxide anion in VEGF/uPAR expression and BRB breakdown in diabetes. Studies were performed in streptozotocin diabetic rats and mice and high glucose (HG) treated REC. The superoxide dismutase (SOD) mimetic tempol blocked diabetes-induced permeability and uPAR expression in rats and the cell permeable SOD inhibited HG-induced expression of uPAR and VEGF in REC. Inhibiting VEGFR blocked HG-induced expression of VEGF and uPAR and GSK-3β phosphorylation in REC. HG caused β-catenin translocation from the plasma membrane into the cytosol and nucleus. Treatment with HG-conditioned media increased REC paracellular permeability that was blocked by anti-uPA or anti-uPAR antibodies. Moreover, deletion of uPAR blocked diabetes-induced BRB breakdown and activation of MMP-9 in mice. Together, these data indicate that diabetes-induced oxidative stress triggers BRB breakdown by a mechanism involving uPAR expression through VEGF-induced activation of the GSK3β/β-catenin signaling pathway.

Cellular and Molecular Mechanisms of Retinal Angiogenesis

Angiogenesis is a multi-factorial process that involves different cell types and a number of cytokines and growth factors. Physiological angiogenesis is characterized by the existence of a delicate balance between pro-angiogenic and anti-angiogenic factors. In an in vivo setting, pro-angiogenic stimuli such as endothelial-specific mitogenic factors and extracellular matrix (ECM)- degrading enzymes must be tightly regulated and locally constrained. Differentiation factors, protease inhibitors, and the elements involved in reconstruction of ECM and recruitment of mural cells must be elicited in an appropriate temporal and spatial arrangement. Overexpression of angiogenesis-activating factors may cause hyper-vascularization. However, deficiency or disarray in expression of anti-angiogenic factors may result in leaky vessels, unstable capillaries, and formation of dysfunctional neovascular tufts as seen in retinopathy of prematurity, diabetic retinopathy, or other conditions of retinal neovascularization. In other words, pathological angiogenesis is characterized not only by excesses in pro-angiogenic factors but also an insufficiency in anti-angiogenic, pro-differentiation factors.

Correction: Diabetes-induced superoxide anion and breakdown of the blood-retinal barrier: Role of the VEGF/uPAR pathway (PLoS ONE (2013) 8:8 (e71868) DOI: 10.1371/journal.pone.0071868)

[This corrects the article DOI: 10.1371/journal.pone.0071868.].