The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis.
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.
Sapieha
Przemyslaw
P
Research Center of Centre Hospitalier Universitaire Sainte-Justine, Department of Pediatrics, Université de Montréal, Montreal, Quebec H3T 1C5, Canada.
Sirinyan
Mirna
M
Hamel
David
D
Zaniolo
Karine
K
Joyal
Jean-Sébastien
JS
Cho
Jang-Hyeon
JH
Honoré
Jean-Claude
JC
Kermorvant-Duchemin
Elsa
E
Varma
Daya R
DR
Tremblay
Sophie
S
Leduc
Martin
M
Rihakova
Lenka
L
Hardy
Pierre
P
Klein
William H
WH
Mu
Xiuqian
X
Mamer
Orval
O
Lachapelle
Pierre
P
Di Polo
Adriana
A
Beauséjour
Christian
C
Andelfinger
Gregor
G
Mitchell
Grant
G
Sennlaub
Florian
F
Chemtob
Sylvain
S
D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007511:Ischemia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000502:physiology; D015861:Retinal Neovascularization / Q000209:etiology* / Q000503:physiopathology; D019802:Succinic Acid / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043562:Receptors, G-Protein-Coupled; C523503:Sucnr1 protein, rat; D042461:Vascular Endothelial Growth Factor A; D019802:Succinic Acid