June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Increased vascular permeability in R-Ras knockout mice with hypoxia-induced retinopathy and a lack of R-Ras expression in human diabetic retinal neovasculature
Author Affiliations & Notes
  • Maria Vähätupa
    Department of Anatomy, University of Tampere, Tampere, Finland
    Department of Ophthalmology, University of Tampere, Tampere, Finland
  • Stuart Prince
    Department of Anatomy, University of Tampere, Tampere, Finland
  • Marko Kataja
    Eye Center, Tampere University Hospital, Tampere, Finland
  • Kati Kinnunen
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
  • Hannu M T Uusitalo
    Department of Ophthalmology, University of Tampere, Tampere, Finland
    Eye Center, Tampere University Hospital, Tampere, Finland
  • Masanobu Komatsu
    Cancer Center, Sanford-Burnham Medical Research Institute, Orlando, FL
  • Erkki Ruoslahti
    Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA
  • Tero Järvinen
    Department of Anatomy, University of Tampere, Tampere, Finland
    Department of Musculoskeletal Diseases, Tampere University Hospital, Tampere, Finland
  • Hannele Uusitalo-Järvinen
    Department of Ophthalmology, University of Tampere, Tampere, Finland
    Eye Center, Tampere University Hospital, Tampere, Finland
  • Footnotes
    Commercial Relationships Maria Vähätupa, None; Stuart Prince, None; Marko Kataja, None; Kati Kinnunen, None; Hannu Uusitalo, None; Masanobu Komatsu, None; Erkki Ruoslahti, None; Tero Järvinen, None; Hannele Uusitalo-Järvinen, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4275. doi:
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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, Ophthalmology and Anatomy, University of Tampere; 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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

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.

 
Methods
 

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.

 
Results
 

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).

 
Conclusions
 

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.  

 
Fig1. Vessel permeability is increased in R-Ras KO mice in OIR after 1h (B) and 24 hrs (A and C) of Evans Blue dye circulation.
 
Fig1. Vessel permeability is increased in R-Ras KO mice in OIR after 1h (B) and 24 hrs (A and C) of Evans Blue dye circulation.
 
 
Fig2. (A) Number of R-Ras+ vessels in diabetic neovascular membranes (n=8). (B) R-Ras and VEGFR2 shows a strong inverse correlation (r = -0,783, p = 0,011). (C) Samples of high (patient #1) and low (#2) R-Ras expression. (D) A majority of vessels in patient #3 are R-Ras+ and VEGFR2−, whereas the situation is reversed in patient # 4.
 
Fig2. (A) Number of R-Ras+ vessels in diabetic neovascular membranes (n=8). (B) R-Ras and VEGFR2 shows a strong inverse correlation (r = -0,783, p = 0,011). (C) Samples of high (patient #1) and low (#2) R-Ras expression. (D) A majority of vessels in patient #3 are R-Ras+ and VEGFR2−, whereas the situation is reversed in patient # 4.

 
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