Metabolic Reprogramming of the Neovascular Niche Promotes Regenerative Angiogenesis in Proliferative Retinopathy

Healthy blood vessels supply neurons to preserve metabolic function. In blinding ischemic proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological neuroretina revascularization. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy between healthy and diseased blood vessel growth. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3 , an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. Highlights 1. Pathological EC favor FAO over glycolysis. 2. Unique signature for pathological EC found in proliferative retinopathy model. 3. Sirt3 deletion shifts astrocytes and EC metabolism from FAO to glycolysis. 4. Metabolic reprogramming of the vascular niche enhances physiological revascularization. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * DR : Diabetic retinopathy PR : Proliferative retinopathies PDR : Proliferative diabetic retinopathies NV : Neovascularization OIR : Oxygen-induced retinopathy VO : Vaso-obliteration EC : Endothelial cells NVT : Neovascular tuft P14 : Post-natal day 14 P17 : Post-natal day 17 FAO : Fatty acid beta-oxidation 2-DG : 2-deoxyglucose ERG : Electroretinography GSVA : Gene set variation analysis DEGs : Differentially expressed genes Sirt3 : Sirtuin-3 Cpt1 : Carnitine palmitoyltransferase 1 Acadl : Acyl-CoA dehydrogenase Acadvl : Very long-chain specific acyl-CoA dehydrogenase Hadh : Hydroxyacyl-Coenzyme A dehydrogenase Hadha : Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Alpha Hadhb : Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta Pecam1 : Platelet and Endothelial Cell Adhesion Molecule 1 Esm1 : Endothelial Cell-Specific Molecule 1 Aqp1 : Aquaporin 1 Col18a1 : Collagen Type XVIII Alpha 1 Chain Col15a1 : Collagen Type XV Alpha 1 Chain Pkm : Pyruvate Kinase M1/2 Aldoa : Aldolase, Fructose-Bisphosphate A Tpi1 : Triosephosphate Isomerase 1 Gpi1 : Glucose-6-Phosphate Isomerase [1]: pending:yes