Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

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
PMCID: PMC11584973 (available on 2025-10-01)
DOI: 10.1038/s41589-024-01583-8

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Roshan Kumar et al. Nat Chem Biol. 2024 Oct.

. 2024 Oct;20(10):1294-1304.

doi: 10.1038/s41589-024-01583-8. Epub 2024 Mar 20.

Authors

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
PMCID: PMC11584973 (available on 2025-10-01)
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.

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Update of

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.
Kumar R, Vitvitsky V, Seth P, Hiraki HL, Bell H, Andren A, Singhal R, Baker BM, Lyssiotis CA, Shah YM, Banerjee R. Kumar R, et al. bioRxiv [Preprint]. 2023 Mar 15:2023.03.14.532677. doi: 10.1101/2023.03.14.532677. bioRxiv. 2023. Update in: Nat Chem Biol. 2024 Oct;20(10):1294-1304. doi: 10.1038/s41589-024-01583-8. PMID: 36993187 Free PMC article. Updated. Preprint.

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Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

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Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

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