title: Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, University of Tampere, Tampere, Finland 2Department of Anatomy, University of Tampere, Tampere, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Vähätupa
authors.affiliation: Department of Anatomy, University of Tampere, Tampere, Finland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Prince
authors.affiliation: Department of Ophthalmology, University of Tampere, Tampere, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Vataja
authors.affiliation: Department of Ophthalmology, University of Tampere, Tampere, Finland.
authors.forename: Teija
authors.initials: T
authors.lastname: Mertimo
authors.affiliation: Eye Centre, Tampere University Hospital, Tampere, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Kataja
authors.affiliation: Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kinnunen
authors.affiliation: Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Varpu
authors.initials: V
authors.lastname: Marjomäki
authors.affiliation: Department of Ophthalmology, University of Tampere, Tampere, Finland 3Eye Centre, Tampere University Hospital, Tampere, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Uusitalo
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, Florida, United States.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Anatomy, University of Tampere, Tampere, Finland 7Department of Musculoskeletal Disorders, Tampere University Hospital, Tampere, Finland.
authors.forename: Tero A H
authors.initials: TA
authors.lastname: Järvinen
authors.affiliation: Department of Ophthalmology, University of Tampere, Tampere, Finland 3Eye Centre, Tampere University Hospital, Tampere, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Uusitalo-Järvinen