Regulation of retinal angiogenesis by a novel lactate receptor, GPR81

Background: Ischemic proliferative retinopathies as characterized by an exaggerated retinal neovascularization, are the 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. Moreover, increase in lactic acid production has long been associated with angiogenesis in tumors. 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, we investigated the propensity of lactate to regulate retinal vessel growth via GPR81.;Hypothesis: We hypothesized that lactate may play an important role in the development of ischemia-induced retinal neovascularization by acting through specific cognate receptor GPR81.;Methods: Lactate levels were measured by a colorimetric assay in retinas of mice exposed to oxygen-induced retinopathy (OIR) model. GPR81 mRNA was analyzed by RT-PCR in the retina of mice exposed to OIR and in Retinal Ganglion Cells (RGC) and retinal endothelial cell cultures. GPR81 protein localization was evaluated by co-immunostaining with cell-specific markers in retinal cryosections. Pro-angiogenic response to lactate was measured in vitro by using endothelial cell tube formation assay and in vivo by analyzing the vascular density in retinal flatmounts of mice pups injected intravitreally with lactate.;Results: Lactate concentration increased 2.5 times in the retinas at P17 in animals exposed to OIR model compared to the control. GPR81 mRNA was detected in the mice retina and the cell cultures analyzed. The GPR81 protein was predominantly localized in the ganglion cells, endothelium and Muller Cells in the retina. Lactate showed a pro-angiogenic effect at 10 mM in the endothelial cell assay and a significant increase (p<0.05) in the retinal vascular density.;Conclusions: Our result suggest that the pro-angiogenic metabolite lactate produced during neovascularization phase in the OIR model acting via its GPR81 receptor expressed in the retina, may play an important role in the development of vasoproliferative retinopathies.