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BackgroundThe surprising discovery that the diatomic gas nitric oxide (NO) is generated by mammalian cells and serves to regulate a multitude of physiological processes has continued to fascinate biologists for almost four decades. The biochemistry of NO is extremely complex, and novel insights into the control of NO biosynthesis and mechanisms of signal transduction are still emerging. AimTo explore a novel idea on how NO synthase activity is transduced and to study the role of host microbiota and the red blood cell in NO signaling.  Work planHere we test the controversial idea that NO synthase activity is not primarily transduced via the release of free NO but instead a complex of NO and heme, termed NO-ferroheme. The bioactivity of NO-ferroheme species is tested in vascular bioassays and in vivo in rodents and the role of endogenously generated NO-ferroheme is explored. The role of the microbiota in the generation of novel NO-related signaling species is also explored, as is the red blood cell and its fascinating ability to release NO bioactivity to protect tissues from ischemia-reperfusion injury.SignificanceNO is a key regulator of cardiovascular function and aberrant NO signaling is a central feature of many major disorders. We are hoping that the novel mechanisms for NO bioactivity transduction explored here will facilitate the development of novel means of increasing NO bioactivity with therapeutic and nutritional implications