Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Angiogenic programming in the vascular endothelium is a tightly regulated process to maintain tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Herein, we report that hypoxic upregulation of NO synthesis in endothelial cells reprograms the transsulfuration pathway and increases H2S biogenesis. Furthermore, H2S oxidation by mitochondrial sulfide quinone oxidoreductase (SQOR) rather than downstream persulfides, synergizes with hypoxia to induce a reductive shift, limiting endothelial cell proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body WBCreSQORfl/fl knockout mice exhibit lower mass and reduced angiogenesis compared to SQORfl/fl controls. WBCreSQORfl/fl mice also exhibit reduced muscle angiogenesis following femoral artery ligation, compared to controls. Collectively, our data reveal the molecular intersections between H2S, O2 and NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization. HighlightsO_LIHypoxic induction of *NO in endothelial cells inhibits CBS and switches CTH reaction specificity C_LIO_LIHypoxic interruption of the canonical transsulfuration pathway promotes H2S synthesis C_LIO_LISynergizing with hypoxia, SQOR deficiency induces a reductive shift in the ETC and restricts proliferation C_LIO_LISQOR KO mice exhibit lower neovascularization in tumor xenograft and hind limb ischemia models C_LI