Journal Article

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

Beauséjour, Christian, Andelfinger, Gregor, Lachapelle, Pierre, Zaniolo, Karine, Sennlaub, Florian, Hardy, Pierre, Sirinyan, Mirna, Cho, Jang-Hyeon, Leduc, Martin, Joyal, Jean-Sébastien, Mitchell, Grant, Varma, Daya R, Klein, William H, Di Polo, Adriana, Honoré, Jean-Claude, Mu, Xiuqian, Rihakova, Lenka, Mamer, Orval, Chemtob, Sylvain, Sapieha, Przemyslaw, Kermorvant-Duchemin, Elsa, Hamel, David, Tremblay, Sophie

2008

Overview

The mechanisms that control blood vessel formation are incompletely understood. Sylvain Chemtob and his colleagues now find that blood vessel formation in mouse and rat retinas is controlled by succinate generated during hypoxic and ischemic conditions. Succinate acting through its receptor, GPR91, on retinal ganglion neurons, triggers secretion of canonical proangiogenic factors and the formation of new blood vessels to reinstate adequate tissue supply. This work also identifies GPR91 as a potential therapeutic target for the treatment of ischemic retinopathies. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Angiogenesis / Animals / Biochemistry / Biomedicine / Cancer Research / Cell receptors / Control / Health aspects / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - physiology / Infectious Diseases / Ischemia - metabolism / Metabolic Diseases / Metabolism / Metabolites / Molecular Medicine / Neovascularization / Neurons / Neurosciences / Physiological aspects / Rats / Rats, Sprague-Dawley / Receptors, G-Protein-Coupled - analysis / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - physiology / Retina / Retina - physiology / Retinal degeneration / Retinal Ganglion Cells - physiology / Retinal Neovascularization - etiology / Retinal Neovascularization - physiopathology / Rodents / Sensors / Signal transduction / Succinic Acid - metabolism / Vascular Endothelial Growth Factor A - physiology