NOS3 Gene: Endothelial Nitric Oxide Synthase (eNOS) – Function, Mutations, and Clinical Significance

The NOS3 gene encodes endothelial nitric oxide synthase (eNOS), a calcium/calmodulin-dependent enzyme that produces nitric oxide (NO) from L-arginine. eNOS-derived NO is a critical signaling molecule in the cardiovascular system, regulating vasodilation, platelet aggregation, leukocyte adhesion, and vascular smooth muscle proliferation. NOS3 is predominantly expressed in endothelial cells and plays a central role in maintaining vascular homeostasis. Genetic variants in NOS3 are associated with altered NO bioavailability and susceptibility to hypertension, coronary artery disease, and other vascular disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• hsa:04022 – cGMP-PKG signaling pathway

• hsa:04270 – Vascular smooth muscle contraction

• hsa:04370 – VEGF signaling pathway

• hsa:04614 – Renin-angiotensin system

• hsa:04933 – AGE-RAGE signaling pathway in diabetic complications

Endothelial nitric oxide synthase (eNOS) is a 133 kDa protein encoded by NOS3. It contains an N-terminal oxygenase domain with binding sites for heme, tetrahydrobiopterin (BH4), and L-arginine, and a C-terminal reductase domain that binds FAD, FMN, and NADPH. eNOS functions as a homodimer and requires calcium/calmodulin for activation. Post-translational modifications (e.g., myristoylation, palmitoylation) target eNOS to caveolae in endothelial cell membranes. The enzyme produces NO, which diffuses to adjacent smooth muscle cells, activating soluble guanylyl cyclase and increasing cGMP, leading to vasodilation. Dysregulation of eNOS (e.g., uncoupling) contributes to oxidative stress and endothelial dysfunction.