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Francois Duhamel, Karine Zaniolo, Houda Tahiri, Sylvain Chemtob; Role of the Krebs Cycle metabolite α-ketoglutarate and its receptor, GPR99, in retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):605.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP), a major cause of blindness in developed countries, occurs in two phases: the cessation of normal eye development after birth and a subsequent abnormal and exaggerated vessel growth. Peripheral hypoxia occurs after the first phase in premature eye and induces production of many growth factors implicated in this second destructive neovascularization phase. Our laboratory has previously demonstrated the role of succinate/GPR91 in the modulation of retinal vessel growth. Here, we investigated the role of α-ketoglutarate and its cognate receptor GPR99 in retinal angiogenesis.
Effects of α-ketoglutarate on developmental retinal vascularisation were assessed following intravitreal injection of Sprague-Dawley rat pups in development. Moreover, the effects of a siGPR99 knockdown following intravitreal injection were investigated in the neovascular phase of ROP. Endogenous expression of retinal GPR99 was assessed by immunohistochemistry on retina cuts and Western blots analysis of different cell lines while expression of pro-angiogenic factors was assessed by PCR analysis. The ability of α-ketoglutarate to promote vessel sprouting was determined by aortic rings cultures.
α-ketoglutarate significantly enhanced developmental vascular densities at different time points. Neovascularization was blocked by a siGPR99 and allowed normal vessel growth in ROP. Moreover, GPR99 was robustly expressed in RGCs as confirmed by co-labeling with neuron markers and, in vitro, mainly in neuronal cells. Conditioned media from α-ketoglutarate stimulated-neurons induced aortic rings sprouting, in correlation with an up-regulation of pro-angiogenic factors expression.
Our results disclose a pro-angiogenic role for α-ketoglutarate and its receptor, GPR99, providing increasing supports for the involvement of metabolite signalling in ischemic conditions.
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