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.
Research Center of Centre Hospitalier Universitaire Sainte-Justine, Department of Pediatrics, Université de Montréal, Montreal, Quebec H3T 1C5, Canada.
Przemyslaw
P
Sapieha
Mirna
M
Sirinyan
David
D
Hamel
Karine
K
Zaniolo
Jean-Sébastien
JS
Joyal
Jang-Hyeon
JH
Cho
Jean-Claude
JC
Honoré
Elsa
E
Kermorvant-Duchemin
Daya R
DR
Varma
Sophie
S
Tremblay
Martin
M
Leduc
Lenka
L
Rihakova
Pierre
P
Hardy
William H
WH
Klein
Xiuqian
X
Mu
Orval
O
Mamer
Pierre
P
Lachapelle
Adriana
A
Di Polo
Christian
C
Beauséjour
Gregor
G
Andelfinger
Grant
G
Mitchell
Florian
F
Sennlaub
Sylvain
S
Chemtob
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