Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Area of Science:

• Cellular Metabolism
• Molecular Biology
• Physiology

Background:

• Angiogenesis regulation in vascular endothelium is crucial for homeostasis, tissue injury, and tumor microenvironments.
• The metabolic mechanisms by which gas signaling molecules influence angiogenesis remain unclear.

Approach:

• Investigated the role of hypoxia-induced nitric oxide (NO) in reprogramming the transsulfuration pathway and hydrogen sulfide (H ₂ S) biogenesis in endothelial cells.
• Examined the function of mitochondrial sulfide quinone oxidoreductase (SQOR) in H ₂ S oxidation and its impact on endothelial cell proliferation under hypoxic conditions.
• Utilized whole-body WB^Cre SQOR^fl/fl knockout mice to assess the in vivo effects on tumor angiogenesis and hind limb ischemia models.

Key Points:

• Hypoxic upregulation of NO synthesis reprograms the transsulfuration pathway, increasing H ₂ S biogenesis in endothelial cells.
• H ₂ S oxidation by SQOR, in conjunction with hypoxia, induces a reductive shift in the mitochondrial electron transport chain, limiting endothelial cell proliferation.
• Pharmacological or genetic inhibition of SQOR significantly reduces tumor growth and neovascularization, as well as muscle angiogenesis in a hind limb ischemia model.

Conclusions:

• Revealed molecular intersections between hydrogen sulfide (H ₂ S), oxygen (O ₂), and nitric oxide (NO) metabolism in regulating endothelial cell function.
• Identified SQOR inhibition as a metabolic vulnerability that can be targeted to restrict endothelial cell proliferation and neovascularization in pathological conditions.