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Second messengers are small, nonprotein intracellular molecules that amplify signals generated by cell-surface receptors. One such messenger, 3′,5′-cyclic guanosine monophosphate (cGMP), plays a central role in transducing extracellular signals into diverse physiological responses. Intracellular cGMP levels are tightly regulated by the opposing actions of guanylate cyclases, which synthesize cGMP from guanosine-5′-triphosphate, and phosphodiesterases (PDEs), which hydrolyze cGMP to inactive 5′-GMP and terminate signaling. Elevated cGMP activates protein kinase G and downstream effectors, thereby driving key physiological processes, including vasodilation. cGMP signaling is essential for a broad range of functions, including synaptic transmission in vision, vascular homeostasis, and smooth muscle relaxation. Pharmacological targeting of the cGMP pathway has produced several successful therapies. Sildenafil (Viagra) enhances cGMP signaling by inhibiting cGMP-specific PDEs. More broadly, modulation of cGMP signaling underlies approved treatments for erectile dysfunction, pulmonary hypertension, heart failure, irritable bowel syndrome, coronary artery disease, and achondroplasia, highlighting the translational significance of this pathway.[1][2]

Dysregulation of cGMP signaling constitutes a central mechanism underlying many cardiovascular diseases and is increasingly described as a “cGMPopathy.” In the pulmonary vasculature, cGMP is essential for the relaxation of vascular smooth muscle. Activation of PKGI and PKGII lowers intracellular calcium by opening calcium-activated potassium channels, stimulating sarcoplasmic reticulum calcium-transporting adenosine triphosphatases, and inhibiting ρ kinase, thereby promoting vasodilation.[25] Impairment of this pathway contributes directly to pulmonary hypertension, in which reduced nitric oxide bioavailability, oxidative inhibition of SGC, or enhanced PDE5-mediated cGMP degradation limit PKG activation and favor vasoconstriction. In heart failure, diminished cGMP signaling and resistance to natriuretic peptide pathways drive disease progression in heart failure with either preserved (HFpEF) or reduced ejection fraction. Reduced myocardial PKG activity is characteristic of HFpEF, whereas PDE9A, which regulates nitric oxide–independent cGMP pools, promotes pathological cardiac hypertrophy.[26] Genetic evidence further links impaired nitric oxide–cGMP signaling to atherosclerosis and myocardial infarction, with rare variants in nitric oxide–activated guanylate cyclase and PDE5 associated with increased risk of coronary artery disease. Collectively, these findings identify cGMP signaling as a key therapeutic target in cardiovascular disease.