Nitric oxide (NO) signaling pathway (NO signaling)

The nitric oxide (NO) signaling pathway is a fundamental regulator of vascular homeostasis and tone within the vascular microenvironment [1.1.2, 1.2.1]. It primarily operates through the NO-sGC-cGMP axis, where NO is synthesized by nitric oxide synthases (NOS)—specifically the endothelial isoform (eNOS) in the vasculature—and diffuses to target cells like vascular smooth muscle cells [1.1.2, 1.2.3]. Upon entering these cells, NO binds to its primary receptor, soluble guanylate cyclase (sGC), stimulating the production of cyclic guanosine monophosphate (cGMP) [1.1.2, 1.1.4]. This second messenger activates protein kinase G (PKG), leading to reduced intracellular calcium and subsequent smooth muscle relaxation, which results in vasodilation [1.1.2, 1.2.1]. Beyond its role in blood pressure regulation, NO signaling in the vascular microenvironment modulates angiogenesis, inhibits platelet aggregation, and suppresses inflammatory responses [1.2.1, 1.2.4]. Dysregulation of this pathway, often characterized by reduced NO bioavailability, is a central feature of endothelial dysfunction and contributes to pathologies such as pulmonary arterial hypertension, chronic heart failure, and erectile dysfunction [1.1.2, 1.2.1]. Pharmacological interventions include NO donors (e.g., nitroglycerin), sGC stimulators (e.g., riociguat), and phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), which aim to enhance cGMP signaling to restore vascular health [1.1.2, 1.1.3].

Other names

Nitric oxide signaling/vascular microenvironmentNO/sGC/cGMP pathwayNitric oxide-guanylate cyclase signalingEndothelial-derived relaxing factor (EDRF) signaling

Nitric oxide (NO) signaling involves the production of NO by nitric oxide synthases (NOS), which activates soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. Drugs modulate this pathway by providing exogenous NO (donors), directly stimulating or activating sGC (stimulators/activators), or inhibiting the degradation of cGMP by phosphodiesterase 5 (PDE5 inhibitors).