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Ankush Madaan, David Hamel, Jose Carlos Rivera, Sylvain Chemtob; Regulation of Retinal Angiogenesis by a Novel Lactate Receptor, GPR81. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5576.
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© ARVO (1962-2015); The Authors (2016-present)
ROP is a major cause of visual impairment and blindness in children. Vascularization is essential for development and restoration of tissue integrity following an ischemic injury. Because vascular supply is coupled to tissue energy consumption, a role for metabolic intermediates such as lactate in angiogenesis is conceivable. Increase in lactate production has long been associated with tumor angiogenesis. Given the recent identification of a novel G-protein coupled receptor for lactate, GPR81 and our detection of high levels of lactate in ischemic retina which precedes the aberrant neovascularization in ROP, we investigate the propensity of lactate in development of ischemia-induced retinal neovascularization by acting through its receptor, GPR81.
Lactate levels were measured in retinas of mice exposed to the ROP model of oxygen-induced retinopathy (OIR). GPR81 mRNA was analyzed by RT-PCR in retina of mice exposed to OIR and in Muller Cells, Retinal Ganglion Cells (RGC) and Retinal Endothelial Cells. GPR81 localization was evaluated by co-immunostaining with cell-specific markers in retinal cryosections. Proangiogenic response to lactate was measured in vitro by tube formation assay, ex vivo on aortic explants and in vivo by analyzing vascular density in retinal flatmounts of mice pups injected intravitreally with lactate.
Lactate levels increased 3 fold in retina of mice exposed to OIR as compared to control. GPR81 expression was detected in mice retina and retinal cell lines, predominantly RGC and Muller Cells. GPR81 expression increased 4 fold in the neovascular phase of OIR. Lactate elicited a pro-angiogenic effect, while it also induced a significant increase (p<0.05) in retinal vascular density upon intravitreal injections; effects of lactate were not observed in tissues of GPR81 KO mice. mRNA expression of pro-angiogenic mediators like VEGF, Angiopoietin I, II, HIF 1α increased in cells stimulated with lactate. Pilot results on GPR81 KO show reduced retinal density in age-matched mice during early retinal vascular development.
Lactate exerts pro-angiogenic effects via GPR81, and participates in neovascularization in models of ROP. Hence, it can be surmised that GPR81 plays an instrumental role in regulation of retinal angiogenesis and can be a potential target to alleviate vasoproliferative retinopathies such as ROP and others (e.g of diabetes).
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