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 H 2 S biogenesis. Furthermore, H 2 S 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 WB Cre SQOR fl/fl knockout mice exhibit lower mass and reduced angiogenesis compared to SQOR fl/fl controls. WB Cre SQOR fl/fl mice also exhibit reduced muscle angiogenesis following femoral artery ligation, compared to controls. Collectively, our data reveal the molecular intersections between H 2 S, O 2 and NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization.
Highlights: Hypoxic induction of •NO in endothelial cells inhibits CBS and switches CTH reaction specificity Hypoxic interruption of the canonical transsulfuration pathway promotes H 2 S synthesis Synergizing with hypoxia, SQOR deficiency induces a reductive shift in the ETC and restricts proliferationSQOR KO mice exhibit lower neovascularization in tumor xenograft and hind limb ischemia models.