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Maria Vähätupa, Stuart Prince, Marko Kataja, Kati Kinnunen, Hannu M T Uusitalo, Masanobu Komatsu, Erkki Ruoslahti, Tero Järvinen, Hannele Uusitalo-Järvinen, ; Increased vascular permeability in R-Ras knockout mice with hypoxia-induced retinopathy and a lack of R-Ras expression in human diabetic retinal neovasculature. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4275.
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R-Ras, a small GTPase, has been shown to regulate vascular permeability in tumor vasculature. We hypothesized that R-Ras might have a role in retinal angiogenesis during developmental and hypoxia-induced angiogenesis. To address the role of R-Ras in diabetic retinopathy, its expression was examined in retinal neovascular membranes obtained from human diabetic retinopathy patients.
Wild-type (WT) and R-Ras knockout (KO) C57BL/6 mice were used in oxygen-induced retinopathy (OIR) model which has been described earlier (Smith et al. 1994). R-Ras expression, vascular leakage and pericyte coverage of vessels were analyzed. Neovascular membranes were obtained from diabetic patients who were undergoing vitrectomy.
R-Ras expression was restricted to the retinal vasculature. 7.5-fold increase in R-Ras level was detected in OIR P17 retinas compared to healthy P17 retinas. Retinal vessels devoid of R-Ras were 3 times more permeable than WT controls in OIR (Fig 1). 40 % reduction in the direct physical contact between pericytes and endothelial cells was found in KO mice. Rate of developmental or hypoxia-induced retinal angiogenesis was not affected by R-Ras. 40 % of angiogenic blood vessels in diabetic neovascular membranes do not express R-Ras (Fig. 2A) and R-Ras expression correlated negatively with VEGFR2 expression (Fig 2B).
R-Ras deficiency results in increased vascular permeability in OIR by impairing pericyte coverage of angiogenic blood vessels. Immature angiogenic blood vessels show dramatically reduced expression of R-Ras in diabetic neovascular membranes suggesting that R-Ras may have a role in controlling vessel maturation in proliferative diabetic retinopathy. Thus, R-Ras could be a potential target to address retinal pathologies related to vascular immaturity and edema.
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