Dear Colleagues,

Almost 30 years after being proclaimed “molecule of the year” in 1992, the fascinating nature of nitric oxide (NO) continues to fuel research in the fields of physiology, immunology, neuroscience, and cardiology. NO is a diatomic, amphipathic, free-radical gaseous mediator with very short half-life whose availability depends on the timed activation of dedicated enzymes (NO synthases). In vessels, the impaired production of NO by the endothelial NO synthase (eNOS) isoform leads to endothelial dysfunction—a condition which precedes and promotes cardiovascular damage. Physiological production of NO by eNOS depends on multiple interrelated steps involving compartmentalization, dimerization, and intracellular Ca²⁺ and phosphorylation-mediated mechanisms, in the presence of sufficient substrates and specific co-factors. This complex machinery may derange under pathophysiological conditions: for example, in a process defined as NOS uncoupling, eNOS may be converted from a NO producing enzyme to an enzyme that generates superoxide (O₂^•−). In recent years, the discovery of a non-canonical pathway for NO generation known as the nitrate–nitrite–NO pathway has further broadened the number of players regulating NO production in vessels. Concomitantly, the identification of eNOS as a nitrite reductase under hypoxia and anoxia suggests that this enzyme, utilizing distinct substrates according to the environmental conditions, may be equipped to produce NO under the full spectrum of oxygen tension experienced in vivo.

Understanding the dynamic interchange between multiple players that modulate the eNOS activity is fundamental to unravelling novel mechanisms and identifying potential pharmacological targets for the treatment and prevention of several cardiovascular disturbances.

This Special Issue is open to all investigations exploring the molecular components of this pathway, or aiming at elucidating alternative targets for this pathway, in order to clarify their impact in experimental models and provide preliminary findings to clinical translation. 

Prof. Dr. Monica Montagnani
Guest Editor

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• Nitric oxide (NO)
• Endothelial NO synthase (eNOS)
• NO-related drugs
• Oxidative stress
• Antioxidants
• Endothelial dysfunction
• Cardiovascular diseases