Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy
Vähätupa, M., Prince, S., Vataja, S., Mertimo, T., Kataja, M., Kinnunen, K., Marjomäki, V., Uusitalo, H., Komatsu, M., Järvinen, T. A., & Uusitalo–Järvinen, H. (2016). Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy. Investigative Ophthalmology and Visual Science, 57(11), 4898-4909. https://doi.org/10.1167/iovs.16-19212
Published inInvestigative Ophthalmology and Visual Science
© the Authors, 2016. This is an open access article licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
PURPOSE. The role of R-Ras in retinal angiogenesis and vascular permeability was evaluated in an oxygen-induced retinopathy (OIR) model using R-Ras knockout (KO) mice and in human diabetic neovascular membranes. METHODS. Mice deficient for R-Ras and their wild-type (WT) littermates were subjected to 75% oxygen from postnatal day 7 (P7) to P12 and then returned to room air. At P17 retinal vascularization was examined from whole mounts, and retinal vascular permeability was studied using Miles assay. Real-time RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of R-Ras in retina during development or in the OIR model. The degree of pericyte coverage and vascular endothelial (VE)-cadherin expression on WT and R-Ras KO retinal blood vessels was quantified using confocal microscopy. The correlation of R-Ras with vascular endothelial growth factor receptor 2 (VEGFR2) and human serum albumin on human proliferative diabetic retinopathy membranes was assessed using immunohistochemistry. RESULTS. In retina, R-Ras expression was mostly restricted to the vasculature. Retinal vessels in the R-Ras KO mice were significantly more permeable than WT controls in the OIR model. A significant reduction in the direct physical contact between pericytes and blood vessel endothelium as well as reduced VE-cadherin immunostaining was found in R-Ras–deficient mice. In human proliferative diabetic retinopathy neovascular membranes, R-Ras expression negatively correlated with increased vascular leakage and expression of VEGFR2, a marker of blood vessel immaturity. CONCLUSIONS. Our results suggest that R-Ras has a role in controlling retinal vessel maturation and stabilization in ischemic retinopathy and provides a potential target for pharmacologic manipulation to treat diabetic retinopathy. ...