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

The Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is a fundamental signal transduction mechanism that regulates vascular homeostasis, muscle relaxation, and platelet function (Cells, 2021). The process begins when nitric oxide (NO), an endogenous gas, binds to the prosthetic heme group of the enzyme soluble guanylate cyclase (sGC) (Physiological Reviews, 2018). This interaction catalyzes the conversion of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), a potent second messenger that activates protein kinase G (PKG) (Nature Reviews Drug Discovery, 2017). PKG subsequently mediates physiological effects such as vasodilation and inhibition of smooth muscle cell proliferation (British Journal of Pharmacology, 2018). Dysregulation of this pathway, often characterized by endothelial dysfunction or oxidative stress that renders sGC insensitive to NO, is central to the pathogenesis of pulmonary arterial hypertension and heart failure (JCI Insight, 2022). Therapeutic strategies targeting this pathway include sGC stimulators like riociguat and vericiguat, which enhance cGMP production, and PDE5 inhibitors like sildenafil, which prevent its breakdown (StatPearls, 2023).

Other names

NO/sGC/cGMP axisNitric oxide signaling pathwayGuanylate cyclase signaling cascadeNO-sGC-cGMP signaling system

Pharmacological modulation involves stimulating or activating soluble guanylate cyclase to increase cGMP production, or inhibiting phosphodiesterase-5 to prevent cGMP degradation, thereby promoting vasodilation and reducing vascular resistance.