Metabolic pathways involved in retinal angiogenesis: Molecular mechanisms and therapeutic targets

Cell metabolism represents a promising and novel therapeutic target for pathological retinal angiogenesis. Cellular metabolic regulatory networks comprise six core synergistic pathways-the glucose, lipid, amino acid, nucleotide, heme, and vitamin D metabolism axes-and disbalances between these can cause various abnormalities and pathogenic conditions, including retinal angiogenesis in blinding retinal disorders. With regard to glucose metabolism, glucose transporters supply substrates, while rate-limiting enzymes regulate glycolytic flow, adenosine triphosphate generation, redox balance, and the supply of nucleotide precursors. Both the transporters and enzymes have a synergistic influence on endothelium-dependent angiogenesis. Lipid metabolism provides dual regulatory targets in retinal angiogenesis via the fatty acid β-oxidation pathway driven by carnitine palmitoyltransferase-1α and the de novo lipid synthesis pathway mediated by fatty acid synthase. In the context of amino acid metabolism, the focus is mainly on the glutamine and arginine metabolism axes. Glutamine regulates retinal angiogenesis through a dynamic balance of anabolism/catabolism that involves amino acid transporters, glutaminase, and glutamine synthetase, while arginine metabolism inhibits pathological retinal neovascularization through the arginase-1 and endothelial nitric oxide synthase signaling pathways. The nucleotide synthesis pathway regulates pyrimidine metabolic flow through key enzymes such as carbamoyl phosphate synthetase II, which maintains tip cell differentiation through dynamic regulation of Notch signaling. Finally, the heme oxygenase-1/carbon monoxide metabolism axis and vitamin D receptor signaling have recently been shown to have unique roles in retinal angiogenesis. This review highlights the main facets of these six metabolic pathways involved in retinal angiogenesis and addresses the potential of targeting them to develop novel therapy for pathological retinal angiogenesis.