Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling pathway (NO-sGC-cGMP)

The vascular smooth muscle nitric oxide (NO) pathway is a fundamental signaling cascade responsible for regulating vascular tone, blood pressure, and regional blood flow. The process is initiated when NO, produced primarily by endothelial nitric oxide synthase (eNOS), diffuses into vascular smooth muscle cells and binds to the heme moiety of soluble guanylate cyclase (sGC) (StatPearls, 2023). This binding triggers a conformational change in sGC, significantly increasing its enzymatic activity to convert guanosine triphosphate (GTP) into the second messenger cyclic guanosine monophosphate (cGMP) (PubMed, PMC2824518). Elevated intracellular cGMP then activates protein kinase G (PKG), which promotes the sequestration of calcium into the sarcoplasmic reticulum and inhibits calcium influx, leading to smooth muscle relaxation and subsequent vasodilation (Nature Reviews Cardiology, 2019). Impairment of this pathway, often termed endothelial dysfunction, is a hallmark of cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. Therapeutic strategies targeting this pathway include NO donors like nitroglycerin, sGC stimulators like riociguat, and phosphodiesterase-5 (PDE5) inhibitors like sildenafil, which prevent the degradation of cGMP (Circulation, 2017).

Other names

Nitric oxide-soluble guanylate cyclase-cGMP pathwayNO-sGC-cGMP signaling pathwayEndothelium-derived relaxing factor pathwayVascular NO signaling

Activation of soluble guanylate cyclase by nitric oxide or direct stimulators, leading to increased cyclic guanosine monophosphate (cGMP) levels, which activates protein kinase G to induce vascular smooth muscle relaxation.