Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 52, Issue 8, Pages 5376-5386Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.10-7152
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Funding
- FFB Canada
- Canadian Institutes of Health Research (CIHR)
- Canadian National Institute for the Blind
- CIHR Frederick Banting and Charles Best Canada Graduate Scholarships
- McGill Systems Biology Training Program
- Foundation Sainte-Justine
- Reseau Fonds de la recherche en sante Quebec (FRSQ) de recherche en sante de la vision
- National Institutes of Health [EY017017, EY017017-S]
- V. Kann Rasmussen Foundation [P01 HD18655]
- Research to Prevent Blindness Senior Investigator Award
- Alcon Research Institute Award
- RoFAR
- MacTel Foundation
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PURPOSE. Vascular degeneration and the ensuing abnormal vascular proliferation are central to proliferative retinopathies. Given the metabolic discordance associated with these diseases, the authors explored the role of ghrelin and its growth hormone secretagogue receptor 1a (GHSR-1a) in proliferative retinopathy. METHODS. In a rat model of oxygen-induced retinopathy (OIR), the contribution of ghrelin and GHSR-1a was investigated using the stable ghrelin analogs [Dap3]-ghrelin and GHRP6 and the GSHR-1a antagonists JMV-2959 and [D-Lys3]-GHRP-6. Plasma and retinal levels of ghrelin were analyzed by ELISA, whereas retinal expression and localization of GHSR-1a were examined by immunohistochemistry and Western blot analysis. The angiogenic and vasoprotective properties of ghrelin and its receptor were further confirmed in aortic explants and in models of vaso-obliteration. RESULTS. Ghrelin is produced locally in the retina, whereas GHSR-1a is abundantly expressed in retinal endothelial cells. Ghrelin levels decrease during the vaso-obliterative phase and rise during the proliferative phase of OIR. Intravitreal delivery of [Dap3]-ghrelin during OIR significantly reduces retinal vessel loss when administered during the hyperoxic phase. Conversely, during the neovascular phase, ghrelin promotes pathologic angiogenesis through the activation of GHSR-1a. These angiogenic effects were confirmed ex vivo in aortic explants. CONCLUSIONS. New roles were disclosed for the ghrelin-GHSR-1a pathway in the preservation of retinal vasculature during the vaso-obliterative phase of OIR and during the angiogenic phase of OIR. These findings suggest that the ghrelin-GHSR-1a pathway can exert opposing effects on retinal vasculature, depending on the phase of retinopathy, and thus holds therapeutic potential for proliferative retinopathies. (Invest Ophthalmol Vis Sci. 2011; 52:5376-5386) DOI: 10.1167/iovs.10-7152
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