Nitric oxide (NO) is considered one of the most important protective factors in the vascular system. It dilates blood vessels, lowers blood pressure and protects the vessel walls. However, researchers from Mainz, Frankfurt and Heidelberg have now shown that persistently elevated NO levels can also trigger unexpected adverse reactions. The study was published in Redox Biology.
The study focuses on red blood cells. These not only transport oxygen but also produce nitric oxide. The researchers studied mice whose red blood cells lacked the enzyme arginase-1. As a result, more of the amino acid arginine was available for the production of nitric oxide. The animals showed elevated nitrite levels in the blood as well as lower mean and diastolic blood pressure readings.
Surprisingly, the vessel wall relaxed less effectively despite the elevated NO levels. Both large vessels and small resistance arteries showed a reduced response to acetylcholine, a key trigger of endothelium-dependent vasodilation.
The researchers identified the cause as a counter-regulatory mechanism in endothelial cells, i.e. the cells lining the inside of blood vessels. In these cells, there was increased production of the enzyme GSNOR, which removes so-called S-nitrosyl groups from proteins. This altered key signalling pathways is involved in regulating vascular function.
“Our findings show that chronically elevated NO levels trigger complex adaptive mechanisms in blood vessels,” says Katrin Schäfer of Mainz University Medical Centre, the study’s corresponding author. “Higher NO levels do not automatically equate to better vascular function.”
Interestingly, the impaired vascular relaxation was restored by inhibiting GSNOR. This suggests that the changes observed may be reversible.
This research broadens our understanding of how red blood cells influence vascular function and of the finely tuned regulation of nitric oxide in the circulatory system. In the long term, the findings could also be relevant to conditions associated with impaired vascular function and altered NO metabolism.
Researchers from Mainz University Medical Centre, Goethe University Frankfurt and Heidelberg University were involved in the study. Several of the research groups involved are part of the German Centre for Cardiovascular Research (DZHK).
Original publication:
Gogiraju R, Sun B, Bochenek ML, et al. Loss of erythrocyte arginase-1 impairs vasorelaxation due to endothelial GSNOR overexpression and denitrosylation of G protein subunits. Redox Biol. Published online May 4, 2026. doi:10.1016/j.redox.2026.104201
