Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model

Wenbo Zhang, Harumasa Yokota, Zhimin Xu, Subhadra P. Narayanan, Lauren Yancey, Akitoshi Yoshida, Dennis M. Marcus, Robert W. Caldwell, Ruth B. Caldwell, Steven E. Brooks

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16 Scopus citations

Abstract

Purpose. To investigate the therapeutic use and mechanisms of action of normobaric hyperoxia to promote revascularization and to prevent neovascularization in a mouse model of oxygen-induced ischemic retinopathy. Methods. Hyperoxia treatment (HT, 40%-75% oxygen) was initiated on postnatal day (P) 14 during the pre-proliferative phase of ischemic retinopathy. Immunohistochemistry, ELISA, and quantitative PCR were used to assess effects on retinal vascular repair and pathologic angiogenesis in relation to glial cell injury, VEGF protein, and mRNA levels of key mediators of pathologic angiogenesis. Effects of intravitreal injections of VEGF and the VEGF inhibitor VEGFR1/Fc fusion protein were also studied. Results. Administration of HT during the ischemic pre-proliferative phase of retinopathy effectively accelerated the process of revascularization while preventing the development of vitreous neovascularization. HT enhanced the formation of specialized endothelial tip cells at the edges of the repairing capillary networks and blocked the overexpression of several molecular mediators of angiogenesis, inflammation, and extracellular proteolysis. HT markedly reduced the reactive expression of GFAP in Müller cells and improved the morphology of astrocytes in the avascular region of the retina. Exogenous VEGF administered into the vitreous on P14 was not sufficient to cause vitreous neovascularization in the HT mice. Injection of the VEGF antagonist VEGFR1/Fc blocked both pathologic and physiological angiogenesis and did not rescue astrocytes. Conclusions. HT may be clinically useful to facilitate vascular repair while blocking neovascularization in the pre-proliferative stage of ischemic retinopathy by correcting a broad range of biochemical and cellular abnormalities.

Original languageEnglish (US)
Pages (from-to)6384-6395
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number9
DOIs
Publication statusPublished - Aug 1 2011

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ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Zhang, W., Yokota, H., Xu, Z., Narayanan, S. P., Yancey, L., Yoshida, A., ... Brooks, S. E. (2011). Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model. Investigative Ophthalmology and Visual Science, 52(9), 6384-6395. https://doi.org/10.1167/iovs.11-7666