Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy.

Autor:	Vähätupa M; Department of Ophthalmology, University of Tampere, Tampere, Finland 2Department of Anatomy, University of Tampere, Tampere, Finland., Prince S; Department of Anatomy, University of Tampere, Tampere, Finland., Vataja S; Department of Ophthalmology, University of Tampere, Tampere, Finland., Mertimo T; Department of Ophthalmology, University of Tampere, Tampere, Finland., Kataja M; Eye Centre, Tampere University Hospital, Tampere, Finland., Kinnunen K; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland., Marjomäki V; Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland., Uusitalo H; Department of Ophthalmology, University of Tampere, Tampere, Finland 3Eye Centre, Tampere University Hospital, Tampere, Finland., Komatsu M; Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, Florida, United States., Järvinen TA; Department of Anatomy, University of Tampere, Tampere, Finland 7Department of Musculoskeletal Disorders, Tampere University Hospital, Tampere, Finland., Uusitalo-Järvinen H; Department of Ophthalmology, University of Tampere, Tampere, Finland 3Eye Centre, Tampere University Hospital, Tampere, Finland.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2016 Sep 01; Vol. 57 (11), pp. 4898-4909.
DOI:	10.1167/iovs.16-19212
Abstrakt:	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.
Databáze:	MEDLINE
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