The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis
Autor: | William Klein, Daya R. Varma, Jang Hyeon Cho, Mirna Sirinyan, Grant A. Mitchell, Sylvain Chemtob, Adriana Di Polo, Elsa Kermorvant-Duchemin, Christian Beauséjour, David Hamel, Pierre Hardy, Orval A. Mamer, Florian Sennlaub, Jean-Sébastien Joyal, Sophie Tremblay, Gregor Andelfinger, Martin Leduc, Pierre Lachapelle, Jean Claude Honoré, Lenka Rihakova, Karine Zaniolo, Przemyslaw Sapieha, Xiuqian Mu |
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Rok vydání: | 2008 |
Předmět: |
Retinal Ganglion Cells
Vascular Endothelial Growth Factor A medicine.medical_specialty Angiogenesis Succinic Acid Retinal Neovascularization Biology Retinal ganglion Retina General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled Rats Sprague-Dawley chemistry.chemical_compound Mediator Ischemia Internal medicine Succinate receptor 1 medicine Animals Receptor Retinal General Medicine Hypoxia-Inducible Factor 1 alpha Subunit Rats Cell biology Vascular endothelial growth factor Endocrinology medicine.anatomical_structure chemistry |
Zdroj: | Nature Medicine. 14:1067-1076 |
ISSN: | 1546-170X 1078-8956 |
DOI: | 10.1038/nm.1873 |
Popis: | 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. |
Databáze: | OpenAIRE |
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