Angiogenic programming in the vascular endothelium is a tightly regulated process for maintaining tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Here, we report that hypoxic upregulation of ·NO in endothelial cells reprograms the transsulfuration pathway to increase biogenesis of hydrogen sulfide (H₂S), a proangiogenic metabolite. However, decreased H₂S oxidation due to sulfide quinone oxidoreductase (SQOR) deficiency synergizes with hypoxia, inducing a reductive shift and limiting endothelial proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body (WB^CreSqor^fl/fl) and endothelial-specific (VE-cadherin^Cre-ERT2Sqor^fl/fl) Sqor-knockout mice exhibit lower mass and angiogenesis than control mice. WB^CreSqor^fl/fl mice also exhibit decreased muscle angiogenesis following femoral artery ligation compared to control mice. 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.

血管内皮中的血管生成编程是维持组织稳态的严格调节过程，并在组织损伤和肿瘤微环境中被激活。气体信号分子如何调节血管生成的代谢基础尚不清楚。在此，我们报道内皮细胞中·NO 的缺氧上调会重新编程转硫途径，从而增加硫化氢 (H ₂ S)（一种促血管生成代谢物）的生物发生。然而，由于硫化醌氧化还原酶（SQOR）缺乏而导致的 H ₂ S 氧化减少与缺氧协同作用，诱导还原转变并限制内皮增殖，而内皮增殖因线粒体 NADH 池的消散而减弱。全身 (WB ^Cre Sqor ^fl/fl ) 和内皮特异性 (VE-钙粘蛋白^Cre-ERT2 Sqor ^fl/fl ) Sqor敲除小鼠中的肿瘤异种移植物表现出比对照小鼠更低的质量和血管生成。与对照小鼠相比，WB ^Cre Sqor ^{fl/fl小鼠在股动脉结扎后也表现出肌肉血管生成减少。总的来说，我们的数据揭示了 H} ₂ S、O ₂和·NO 代谢之间的分子交叉，并将 SQOR 抑制确定为内皮细胞增殖和新血管形成的代谢脆弱性。