Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Roshan Kumar; Victor Vitvitsky; Apichaya Sethaudom; Rashi Singhal; Sumeet Solanki; Sydney Alibeckoff; Harrison L Hiraki; Hannah N Bell; Anthony Andren; Brendon M Baker; Costas A Lyssiotis; Yatrik M Shah; Ruma Banerjee

doi:10.1038/s41589-024-01583-8

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Nat Chem Biol. 2024 Mar 20. doi: 10.1038/s41589-024-01583-8. Online ahead of print.

Authors

Roshan Kumar¹, Victor Vitvitsky¹, Apichaya Sethaudom¹, Rashi Singhal², Sumeet Solanki², Sydney Alibeckoff¹, Harrison L Hiraki³, Hannah N Bell², Anthony Andren², Brendon M Baker^{3

4}, Costas A Lyssiotis^{2

5

6}, Yatrik M Shah^{2

5

6}, Ruma Banerjee⁷

Affiliations

¹ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁶ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA. rbanerje@umich.edu.

PMID: 38509349
DOI: 10.1038/s41589-024-01583-8

Abstract

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.

Grants and funding

R01 CA245546/CA/NCI NIH HHS/United States