Lack of R-Ras leads to increased vascular permeability in ischemic retinopathy

Maria Vähätupa, Stuart Prince, Suvi Vataja, Teija Mertimo, Marko Kataja, Kati Kinnunen, Varpu Marjomäki, Hannu Uusitalo, Masanobu Komatsu, Tero A.H. Järvinen, Hannele Uusitalo-Järvinen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4898-4909
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number11
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Retinal Vessels
Capillary Permeability
Diabetic Retinopathy
Oxygen
Blood Vessels
Pericytes
Knockout Mice
Membranes
Retina
Immunohistochemistry
Vascular Endothelial Growth Factor Receptor-2
Confocal Microscopy
Serum Albumin
Endothelium
Real-Time Polymerase Chain Reaction
Western Blotting
Air

Keywords

  • Diabetic retinopathy
  • Neovascularization
  • Retina
  • Retinal ischemia

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Vähätupa, M., Prince, S., Vataja, S., Mertimo, T., Kataja, M., Kinnunen, K., ... 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

Lack of R-Ras leads to increased vascular permeability in ischemic retinopathy. / Vähätupa, Maria; Prince, Stuart; Vataja, Suvi; Mertimo, Teija; Kataja, Marko; Kinnunen, Kati; Marjomäki, Varpu; Uusitalo, Hannu; Komatsu, Masanobu; Järvinen, Tero A.H.; Uusitalo-Järvinen, Hannele.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 11, 01.09.2016, p. 4898-4909.

Research output: Contribution to journalArticle

Vähätupa, M, Prince, S, Vataja, S, Mertimo, T, Kataja, M, Kinnunen, K, Marjomäki, V, Uusitalo, H, Komatsu, M, Järvinen, TAH & Uusitalo-Järvinen, H 2016, 'Lack of R-Ras leads to increased vascular permeability in ischemic retinopathy', Investigative Ophthalmology and Visual Science, vol. 57, no. 11, pp. 4898-4909. https://doi.org/10.1167/iovs.16-19212
Vähätupa, Maria ; Prince, Stuart ; Vataja, Suvi ; Mertimo, Teija ; Kataja, Marko ; Kinnunen, Kati ; Marjomäki, Varpu ; Uusitalo, Hannu ; Komatsu, Masanobu ; Järvinen, Tero A.H. ; Uusitalo-Järvinen, Hannele. / Lack of R-Ras leads to increased vascular permeability in ischemic retinopathy. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 11. pp. 4898-4909.
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abstract = "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.",
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AU - Prince, Stuart

AU - Vataja, Suvi

AU - Mertimo, Teija

AU - Kataja, Marko

AU - Kinnunen, Kati

AU - Marjomäki, Varpu

AU - Uusitalo, Hannu

AU - Komatsu, Masanobu

AU - Järvinen, Tero A.H.

AU - Uusitalo-Järvinen, Hannele

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N2 - 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.

AB - 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.

KW - Diabetic retinopathy

KW - Neovascularization

KW - Retina

KW - Retinal ischemia

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