Expressed in various cell types, Nitric Oxide Synthases (NOS Family) are constitutive or inducible calcium/calmodulin stimulated homodimers stabilized by BH4 that bind FAD and FMN cofactors, generally contain a flavodoxin-like domain, and synthesize reactive free radical nitric oxide messenger from L-arginine. NO can act as a neurotransmitter and has antimicrobial and antitumoral activities in macrophages. IL12 requires NOS to stimulate tyrosine-phosphorylation of STAT4 by TYK2 in NK cytotoxicity. Vascular NO (endothelia) inhibits muscle contraction through a cGMP pathway, inhibits platelet aggregation, and mediates VEGF-induced angiogenesis. Endothelial AKT phosphorylates and enhances NOS activity. Potentially influencing energy balance, NO can trigger cGMP-dependent mitochondrial biogenesis mediated by induction of the master regulator PPARGC1. (NCI)