Discovery reveals how this common stinky gas is processed to promote blood vessel growth

Hydrogen sulfide (H₂S), like many other gases, can be helpful in small doses yet deadly in large amounts. The rotten egg smelling gas is a toxic byproduct of paper milling and sewage treatment industries, as well as a component of volcanic emissions. Yet H₂S is also produced by the human body and by microbes in our gut and is a key player in blood vessel formation.

A new collaborative study from the lab of Ruma Banerjee, Ph.D., a professor in the University of Michigan Medical School Department of Biological Chemistry, examined the interaction between three naturally occurring gases — nitric oxide (NO), oxygen, and H₂S — during generation of new blood vessels, called angiogenesis. 

Blood flow and tumors

In the context of growth and wound healing, angiogenesis is desirable. In the context of cancerous tumors, however, it is problematic. Uncovering the mechanisms behind the body’s use of H₂S could offer a potential target for stopping blood flow to tumors.

“What we stumbled upon was a mechanism that could connect how the known increase in NO under conditions of low oxygen, or hypoxia leads to an increase in H₂S, an important signaling molecule,” said Banerjee.

“As NO goes up, a type of metabolic code switching occurs in the transsulfuration pathway that typically makes the amino acid cysteine. The pathway code switches through a complicated regulatory process to make H₂S instead.” This process is essential for making blood vessels.

Protein deficiency

A protein called sulfide quinone oxidoreductase, or SQOR, helps keep H₂S in balance by oxidizing it and generating energy. To illustrate the importance of SQOR for angiogenesis, the team partnered with Yatrik Shah, Ph.D. in the  Department of Molecular & Integrative Physiology and the Rogel Cancer Center, to generate mouse models of SQOR deficiency. 

Through several experiments led by postdoctoral fellow Roshan Kumar, Ph.D. and involving U-M’s Physiology Phenotyping Core, the team showed that a deficiency of SQOR in conditions of low oxygen led to a reduction in blood vessel generation due to a reduction in mitochondrial energy, both for injury repair following ischemia and in melanoma tumor growth.

“If you make more H₂S under hypoxia but you can’t oxidize it via SQOR, it’s a problem, because it restricts blood vessel formation by endothelial cells,” said Banerjee. “It’s the ability to oxidize H₂S and dump those electrons into the electron transport chain that we’ve discovered is important for new blood vessel biogenesis.”

New targets needed

Traditional therapies to block tumor angiogenesis have so far been unsuccessful.

 “If you inhibit one pathway, cells seem to be able to reroute, so resistance has been a problem. Finding new targets that can be exploited via a multidrug therapy is an important goal,” said Banerjee. The new fundamental findings identify SQOR as a potential novel target for therapeutics.

Additional authors: Include Victor Vitvitsky, Apichaya Sethaudom, Rashi Singhal, Sumeet Solanki, Sydney Alibeckoff, Harrison L. Hiraki, Hannah N. Bell, Anthony Andren, and Brendon M. Baker

Citation: “Sulfide oxidation promotes hypoxic angiogenesis and neovascularization,” Nature Chemical Biology, DOI: 10.1038/s41589-024-01583-8

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