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M. Sapieha, M. Sirinyan, S. Chemtob; Retinal Ganglion Cells Regulate Angiogenesis via Succinate and GPR91. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4458.
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The elevated metabolic demand of neurons such as retinal ganglion cells (RGCs) is supplied by retinal vessels that form (in both physiological and pathological contexts) following the release of hypoxia-triggered pro-angiogenic factors. Although Kreb cycle intermediates such as succinate have long been known to accrue in hypoxic-ischemic states, their contribution to angiogenesis remains ill defined. Given the recent identification of a specific G-protein coupled receptor for succinate (GPR91) as well as our detection of this receptor on RGCs, we investigated the propensity of RGCs to regulate vessel growth via a mechanism involving GPR91 and succinate.
Endogenous expression of retinal GPR91 was examined in Sprague-Dawley rat retinas by western blot and by immunohistochemistry in radial cryosections retrogradely labeled with Fluorogold. The RGC-5 cell line (terminally differentiated with 1µM of staurosporine) served as an ex-vivo model of RGCs. The ability of RGCs to promote vessel sprouting was determined in aortic rings co-cultured with either RGC-5 or RGC-5 conditioned media (with or without succinate treatment). Succinate-induced production of selected pro-angiogenic factors (VEGF, Angiopoietin I & II and PDGF-A) was assessed by real-time PCR in RGC-5 exposed to 100 µM of succinate for 12 hours.
GPR91 was robustly expressed in RGCs as confirmed by co-labeling with Flurogold positive cells. Aortic rings treated with media from RGCs or co-cultured with these neurons showed a significant increase in vessel sprouting. These effects were considerably more pronounced when RGCs were primed with succinate. In line with these findings, we observe that RGCs increase their production of VEGF, Angiopoietin I & II and PDGF-A mRNA following exposure to succinate.
Our data point to a mechanism where in a time of energy mismatch, RGCs, prompted by Kreb cycle intermediates such as succinate, release pro-angiogenic factors. These neurons therefore participate in the recruitment of blood vessels in order to reinstate a metabolic equilibrium.
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