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Ankush Madaan, Jose Carlos Rivera, David Hamel, Sylvain Chemtob; GPR81 (HCA1), a Novel Lactate Receptor, mediates the Development of Inner Vasculature in Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3381.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (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. Since vascular supply is coupled to tissue energy consumption, a role for metabolic intermediates like lactate in angiogenesis is conceivable. Moreover, increase in lactate production has long been associated with tumor angiogenesis and wound repair. 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 investigated the propensity of lactate to regulate retinal vessel growth via GPR81
Lactate levels were measured in retinas of mice exposed to the ROP model of oxygen-induced retinopathy (OIR). GPR81 mRNA was analyzed by quantitative PCR in the retina of mice exposed to OIR. GPR81 expression was evaluated by co-immunostaining with cell-specific markers in retinal cryosections and in retinal cell lines. Pro-angiogenic response to lactate was measured in vitro, ex vivo and in vivo
Lactate levels increased in the retinas of mice exposed to OIR as compared to the control. GPR81 expression was detected in mice retina and retinal cell lines, predominantly in Muller Cells. GPR81 expression increased 4 fold in the neovascular phase of OIR. Lactate elicited a pro-angiogenic effect, as evidenced by tube formation assay, vascular sprouting of aortic explants and a significant increase in the inner retinal vascular density upon intravitreal injections; effects of lactate were not seen in GPR81 KO mice. Expression of pro-angiogenic mediators like VEGF, HIF 1α as well as Norrin (a Wnt pathway ligand) increased in mice retina and cells treated with lactate. GPR81 KO show reduced intraretinal vascular density in age-matched mice in retinal vascular development, associated with down-regulation of Norrin
Our results suggest for the first time that lactate exerts pro-angiogenic effects via GPR81, and participates in intra-retinal vascularization of the retina, including in OIR model of ROP, via regulation of Norrin (known to govern intraretinal vascularization). It can be surmised that GPR81 could be a potential target to alleviate aberrant vasoproliferative retinopathies such as ROP and others (eg. secondary to diabetes)
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