Is NO-ferroheme a signaling entity?

Despite widespread recognition of nitric oxide (NO) synthase (NOS) signaling's biological significance, uncertainties persist regarding the chemical nature of NOS-derived bioactivity. Our research reveals that NO-like bioactivity can efficiently be conveyed by mobile NO-ferroheme species, capable of transferring between proteins, partitioning into a hydrophobic phase, and directly activating the sGC– cGMP–PKG pathway without necessitating free NO intermediacy. These NO-ferroheme species, with or without a protein carrier, effectively relax isolated blood vessels and induce hypotension in rodents, particularly potentiated after NOS activity blockade. Notably, NO-ferroheme-induced relaxations remain unaffected by NO scavengers and blood components, suggesting physiological relevance. Thus, NO-ferroheme emerges as a pivotal signaling entity in vascular physiology.