NO-ferroheme is a signaling entity in the vasculature

Abstract Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species which can exchange proteins, partition to the hydrophobic phase, and directly activate the sGC-cGMP-PKG pathway without the intermediacy of free NO. The NO-ferroheme entity efficiently relaxes isolated blood vessels and induces hypotension in rodents, which is greatly potentiated after blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, NO-ferroheme preserves its vasoactivity, suggesting physiological relevance of these yet underappreciated species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.