Neuronal influence in retinal vascular development. (A) The superficial retinal vascular plexus forms in a stereotyped manner. As the vascular front advances, it leaves perfused RGCs in its wake. (B) The proposed model for RGC-dependent vascularization stipulates that the mildly hypoxic RGCs ahead of the vascular front accumulate energy metabolites such as sucinnate because of the feedback inhibition of succinate dehydrogenase. The elevated levels of succinate then stimulate its RGC-specific cognate receptor GPR91, resulting in the production of proangiogenic cues such as VEGF and Ang-2. RGCs therefore have the inherent ability to instate local microcirculation. (C) The EC₅₀ for succinate-mediated activation of GPR91 is ∼ 10-fold lower than the K_i required for succinate-induced inhibition of prolyl 4-hydroxylases and consequent HIF-1α stabilization. This suggests that succinate through GPR91 acts as an early and accurate sensor of hypoxic stress.