The article by Förstermann and Sessa provides a comprehensive overview of nitric oxide synthases (NOS), the enzymes responsible for producing nitric oxide (NO), a signaling molecule with diverse physiological functions. The three isoforms of NOS—neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)—are discussed in detail, highlighting their structures, mechanisms of action, and roles in various physiological and pathological processes. - **Neuronal NOS (nNOS)**: Constitutively expressed in specific neurons, nNOS is involved in synaptic plasticity, blood pressure regulation, and vasodilation. It is also crucial for penile erection and the action of phosphodiesterase 5 inhibitors. - **Inducible NOS (iNOS)**: Induced by various stimuli, iNOS generates large amounts of NO, which has cytotoxic effects on pathogens and contributes to inflammatory diseases and septic shock. - **Endothelial NOS (eNOS)**: Primarily expressed in endothelial cells, eNOS is essential for maintaining vascular tone, blood pressure, and preventing atherosclerosis. It is regulated by calcium and calmodulin, and its activity can be enhanced by shear stress and phosphorylation. The article also discusses the mechanisms of NO synthesis, the role of cofactors, and the regulation of NOS activity. Additionally, it explores the pathophysiology of cardiovascular diseases, including the role of oxidative stress and eNOS uncoupling, which leads to reduced NO bioavailability and increased vascular damage. Finally, the article reviews therapeutic strategies, such as drugs targeting the renin-angiotensin-aldosterone system and statins, which can improve endothelial function and prevent eNOS uncoupling.The article by Förstermann and Sessa provides a comprehensive overview of nitric oxide synthases (NOS), the enzymes responsible for producing nitric oxide (NO), a signaling molecule with diverse physiological functions. The three isoforms of NOS—neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)—are discussed in detail, highlighting their structures, mechanisms of action, and roles in various physiological and pathological processes. - **Neuronal NOS (nNOS)**: Constitutively expressed in specific neurons, nNOS is involved in synaptic plasticity, blood pressure regulation, and vasodilation. It is also crucial for penile erection and the action of phosphodiesterase 5 inhibitors. - **Inducible NOS (iNOS)**: Induced by various stimuli, iNOS generates large amounts of NO, which has cytotoxic effects on pathogens and contributes to inflammatory diseases and septic shock. - **Endothelial NOS (eNOS)**: Primarily expressed in endothelial cells, eNOS is essential for maintaining vascular tone, blood pressure, and preventing atherosclerosis. It is regulated by calcium and calmodulin, and its activity can be enhanced by shear stress and phosphorylation. The article also discusses the mechanisms of NO synthesis, the role of cofactors, and the regulation of NOS activity. Additionally, it explores the pathophysiology of cardiovascular diseases, including the role of oxidative stress and eNOS uncoupling, which leads to reduced NO bioavailability and increased vascular damage. Finally, the article reviews therapeutic strategies, such as drugs targeting the renin-angiotensin-aldosterone system and statins, which can improve endothelial function and prevent eNOS uncoupling.