Endothelial nitric oxide synthase – Nitric oxide – cyclic Guanosine Monophosphate signaling axis (eNOS-NO-cGMP axis)

The endothelial nitric oxide synthase (eNOS) – Nitric oxide (NO) – cyclic Guanosine Monophosphate (cGMP) signaling axis is a fundamental pathway regulating vascular tone and homeostasis. It begins with the production of NO by eNOS in endothelial cells, which then diffuses into adjacent smooth muscle cells to activate soluble guanylate cyclase (sGC) (UniProt P29474, PubMed: 25634575). This activation leads to the conversion of GTP to cGMP, a second messenger that triggers vasodilation and inhibits platelet aggregation (StatPearls: NBK541080). Dysregulation of this axis is a hallmark of endothelial dysfunction and contributes to various cardiovascular diseases, including hypertension, pulmonary arterial hypertension, and heart failure (PubMed: 29079147). Pharmacological interventions target this pathway through NO donors, sGC stimulators like riociguat, or PDE5 inhibitors like sildenafil to restore vascular function and improve blood flow (NIH: PMC4357518). By increasing the bioavailability or activity of cGMP, these drugs promote smooth muscle relaxation and reduce vascular resistance. This axis also plays a role in angiogenesis and the prevention of leukocyte adhesion to the vessel wall. Therapeutic challenges include managing systemic hypotension and avoiding dangerous drug-drug interactions between different classes of axis-modulating agents.

Other names

eNOS/sGC/cGMP pathwayNitric oxide signaling pathwayEndothelial NO-cGMP axisNOS3-NO-cGMP axis

The axis is targeted by increasing nitric oxide availability via NO donors, directly stimulating soluble guanylate cyclase via sGC stimulators, or inhibiting phosphodiesterase-5 to prevent the degradation of cGMP, thereby promoting vasodilation and vascular health.