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Nature Medicine 14, 1067 - 1076 (2008)
Published online: 5 October 2008 | doi:10.1038/nm.1873

The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis

Przemyslaw Sapieha1,2,10, Mirna Sirinyan1,2,10, David Hamel1, Karine Zaniolo1, Jean-Sébastien Joyal1,2, Jang-Hyeon Cho3, Jean-Claude Honoré1, Elsa Kermorvant-Duchemin4, Daya R Varma2, Sophie Tremblay1, Martin Leduc1, Lenka Rihakova1, Pierre Hardy1, William H Klein3, Xiuqian Mu3, Orval Mamer5, Pierre Lachapelle6, Adriana Di Polo7, Christian Beauséjour1, Gregor Andelfinger1, Grant Mitchell1, Florian Sennlaub4,8,9 & Sylvain Chemtob1

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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