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

被引：300

作者：

Sapieha, Przemyslaw ^{[1
,7
,8
]}

Sirinyan, Mirna ^{[1
,7
,8
]}

Hamel, David ^{[7
,8
]}

Zaniolol, Karine ^{[7
,8
]}

Joyal, Jean-Sebastien ^{[1
,7
,8
]}

Cho, Jang-Hyeon ^{[2
]}

Honore, Jean-Claude ^{[7
,8
]}

Kermorvant-Duchemin, Elsa ^{[3
]}

Varma, Daya R. ^{[1
]}

Tremblay, Sophie ^{[7
,8
]}

Leduc, Martin ^{[7
,8
]}

Rihakova, Lenka ^{[7
,8
]}

Hardy, Pierre ^{[7
,8
]}

Klein, William H. ^{[2
]}

Mu, Xiuqian ^{[2
]}

Mamer, Orval ^{[4
]}

Lachapelle, Pierre ^{[5
,6
]}

Di Polo, Adriana ^{[9
]}

Beausiour, Christian ^{[7
,8
]}

Andelfinger, Gregor ^{[7
,8
]}

Mitchell, Grant ^{[7
,8
]}

Sennlaub, Florian ^{[3
,10
,11
]}

Chemtob, Sylvain ^{[7
,8
]}

机构：

[1] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada

[2] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA

[3] Ctr Rech Cordeliers, Unite Mixte Rech Sci S 872, Inst Natl Sante & Rech Med, F-75006 Paris, France

[4] McGill Univ Montreal, Dept Med, Mass Spectrometry Facil, Quebec City, PQ H3A 1A4, Canada

[5] McGill Univ, Montreal Childrens Hosp, Res Inst, Dept Ophthalmol, Montreal, PQ H3H 1P3, Canada

[6] McGill Univ, Montreal Childrens Hosp, Res Inst, Dept Neurol Neurosurg, Montreal, PQ H3H 1P3, Canada

[7] Univ Montreal, Ctr Hosp Univ St Justine, Res Ctr, Dept Pediat, Montreal, PQ H3T 1C5, Canada

[8] Univ Montreal, Ctr Hosp Univ St Justine, Res Ctr, Dept Pharmacol, Montreal, PQ H3T 1C5, Canada

[9] Univ Montreal, Dept Pathol & Cell Biol, Montreal, PQ H3T 1J4, Canada

[10] Univ Paris 06, Unite Mixte Rech Sci S 872, F-75006 Paris, France

[11] Univ Paris 05, Unite Mixte Rech Sci 872, F-75006 Paris, France

来源：

NATURE MEDICINE | 2008年 / 14卷 / 10期

基金：

加拿大健康研究院;

关键词：

D O I：

10.1038/nm.1873

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1067 / 1076

页数：10

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