27 March 2023

The first medications to correct poor tissue oxygenation are a step closer, scientists in the USA have reported.

Treatments might help sickle cell disease as well as heart failure and peripheral artery disease, researchers said.

A team at Harrington Discovery Institute at University Hospitals (UH) and Case Western Reserve University School of Medicine, Cleveland, Ohio, showed that S-nitrosohemoglobin, a modified version of haemoglobin, senses areas with insufficient oxygen and restores blood flow for oxygenation.

Writing in PNAS, the authors say this is the first time a study has shown that it is nitric oxide – not oxygen – which is the crucial component when comes to delivering oxygen to the tissues. The nitric oxide must be carried by haemoglobin, in the form of S-nitrosohemoglobin, to be effective.

“This opens up an entirely new line of drug development,” said senior study author Professor Jonathan Stamler, of the Harrington Discovery Institute at UH and professor of medicine and biochemistry at UH and Case Western Reserve School of Medicine.

Correcting inadequate tissue oxygenation has been a longstanding goal of medicine, but drugs that improve blood flow have so far failed to improve oxygen delivery.

However, this study has identified S-nitrosohemoglobin as a unique vasodilator that not only opens blood vessels, but also produces major increases in tissue oxygenation.

In both mice and humans – including patients with peripheral artery disease, sickle cell disease, heart failure, stroke and emphysema – impairments in tissue oxygenation correlated with levels of S-nitrosohemoglobin.

“This study shows that you must vasodilate through haemoglobin if you want to get oxygen to tissues, because haemoglobin knows precisely where in the body oxygen is low, and then it adjusts itself to give off the vasodilator nitric oxide in proportion to need,” said Dr Stamler. “Other vasodilators dilate vessels everywhere, and steal blood flow from places that need it most.”

Dr Stamler and colleagues are now developing drugs that modify haemoglobin with nitric oxide to form S-nitrosohemoglobin, increasing tissue oxygenation, even when oxygen levels in the blood are low.


Reynolds JD, Posina K, Zhu L, Jenkins T, Matto F, Hausladen A, Kashyap V, Schilz R, Zhang R, Mannick J, Klickstein L, Premont RT, Stamler JS.  (2023) “Control of tissue oxygenation by S-nitrosohemoglobin in human subjects.” PNAS, doi: 10.1073/pnas.2220769120.

Link: https://www.pnas.org/doi/10.1073/pnas.2220769120

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