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

Abstract

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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Figure 1: Succinate levels rise in the ischemic retina, and GPR91 is strongly and predominantly expressed by retinal ganglion neurons.
Figure 2: Developmental retinal vessel growth is influenced by succinate and GPR91.
Figure 3: Retinal ganglion neurons mediate the proangiogenic effects of succinate via GPR91.
Figure 4: Succinate stimulates the production of proangiogenic factors by RGCs via a HIF-1α-independent pathway.
Figure 5: Retinal ganglion neuron ablation impedes succinate-induced neovascularization in the adult.
Figure 6: GPR91 knockdown protects against retinal neovascularization in ischemic proliferative retinopathy.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research, the March of Dimes Birth Defects Foundation, the Heart and Stroke Foundation of Québec and the Fonds de la Recherche en Santé du Québec. P.S. and M.S. hold a Research Fellowship Award and a studentship from the Heart and Stroke Foundation of Canada, respectively. K.Z. is a recipient of The Foundation Fighting Blindness Postdoctoral Fellowship Award. F.S. and S.C. are recipients of a fellowship and scientist awards, respectively, from the Canadian Institutes of Health Research. S.C. also holds a Canada Research Chair (perinatology). Generation of brn3bZ-dta/+;six3-cre mice and J.-H.C.'s salary were supported by a US National Eye Institute grant EY011930 to W.H.K. and by the Robert A. Welch Foundation (G-0010), respectively. We wish to thank N. Agarwal, from the University of North Texas Health Science Center at Fort Worth, for his kind donation of the RGC-5 cell line. We also wish to thank H. Fernandez and S. Leclerc for valuable technical assistance.

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Correspondence to Sylvain Chemtob.

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Supplementary Figs. 1-4, Supplementary Table 1 and Supplementary Methods (PDF 1751 kb)

Supplementary Video 1

Three-dimensional confocal representation of a 30-μm–thick radial section of the retina. GPR91-positive cells are labeled in green, whereas lectin-stained blood vessels are in red. A lack of overlap indicates that GPR91 is not expressed in retinal blood vessels. (MOV 1060 kb)

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Sapieha, P., Sirinyan, M., Hamel, D. et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 14, 1067–1076 (2008). https://doi.org/10.1038/nm.1873

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