Journal
NATURE MEDICINE
Volume 14, Issue 10, Pages 1067-1076Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.1873
Keywords
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Funding
- Canadian Institutes of Health Research
- March of Dimes Birth Defects Foundation
- Heart and Stroke Foundation of Quebec
- Fonds de la Recherche en Sante du Quebec
- Heart and Stroke Foundation of Canada
- Foundation Fighting Blindness Postdoctoral Fellowship Award
- US National Eye Institute [EY011930]
- Robert A. Welch Foundation [G-0010]
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Vascularization is essential for tissue development and in restoration of tissue integrity after an ischemic injury. in studies of vascularization, the focus has largely been placed on vascular endothelial growth factor (VEGF), yet other factors may also orchestrate this process. Here we show that succinate accumulates in the hypoxic retina of rodents and, via its cognate receptor G protein-coupled receptor-91 (GPR91), is a potent mediator of vessel growth in the settings of both normal retinal development and proliferative ischemic retinopathy. The effects of GPR91 are mediated by retinal ganglion neurons (RGCs), which, in response to increased succinate levels, regulate the production of numerous angiogenic factors including VEGF. Accordingly, succinate did not have proangiogenic effects in RGC-deficient rats. Our observations show a pathway of metabolite signaling where succinate, acting through GPR91, governs retinal angiogenesis and show the propensity of RGCs to act as sensors of ischemic stress. These findings provide a new therapeutic target for modulating revascularization.
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