Müller Cell–Localized GPR81 (HCA1) Regulates Inner Retinal Vasculature via Norrin/Wnt Pathways

Ischemic retinopathies (IRs) are characterized by a progressive microvascular degeneration followed by a post-ischemic aberrant neovascularization. To reinstate vascular supply and metabolic equilibrium to the ischemic tissue during IRs, a dysregulated production of growth factors and metabolic intermediates occurs, promoting retinal angiogenesis. Glycolysis-derived lactate highly produced during ischemic conditions has been associated with tumor angiogenesis and wound healing. Lactate exerts its biologic effects via a G-protein–coupled receptor 81 (GPR81) in several tissues; however, its physiological functions and mechanisms of action in the retina remain poorly understood. Here we show that GPR81 localized predominantly in Muller cells governs deep vascular complex formation during development and in ischemic retinopathy. Lactate-stimulated GPR81 Muller cells produce numerous angiogenic factors including Wnt ligands and particularly Norrin, which contributes significantly in triggering inner retinal blood vessel formation. Conversely, GPR81-null mice retina shows reduced inner vascular network formation associated with low levels of Norrin (and Wnt ligands). Lactate accumulation during IR, selectively activates GPR81-Erk1/2-Norrin signaling to accelerate inner retinal vascularization in WT animals, but not in retina of GPR81-null mice. Altogether, we reveal that lactate via GPR81-Norrin participates in inner vascular network development, and in restoration of the vasculature in response to injury. These findings suggest a new potential therapeutic target to alleviate ischemic diseases.