etes mellitus, hypertension, atherosclerosis, and cerebral ischemia \[[@B22], [@B43]\].

2.1. Posttranslational Modifications of NOS {#sec2.1}
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NOS enzymes are regulated by multiple interdependent mechanisms and signaling pathways, which can be calcium-dependent and/or calcium-independent. In particular, it has been demonstrated that the activity of eNOS is regulated by the increase of the cytosolic Ca^2+^ in endothelial cells, which leads to the activation of calmodulin that in turn binds eNOS, thus facilitating its function \[[@B23], [@B44]\]. Besides the increase of intracellular calcium, eNOS activity depends also on its phosphorylation status. In particular, It has been suggested that the phosphorylation of NOS isoforms at Tyr81 and Tyr657 represents a mechanism necessary to modulate the NO production above all during shear stress \[[@B45], [@B46]\].

Indeed, the phosphorylation is the major and most studied posttranslational modifications influencing the eNOS activity. Noteworthy, while the phosphorylation of serine at positions 617, 635, and 1179/1177 results in the activation of the eNOS, the same change at Ser116 and Thr497 reduces its function.

Also acetylation of the eNOS influences its activity and, in general, acetylation/deacetylation balance represents a crucial homeostatic mechanism mediating the response to metabolic changes in the cell \[[@B47]\].

Other important posttranslational changes are acylation, nitrosylation, glycosylation, and glutathionylation. All of them are necessary and often interconnected in controlling the subcellular localization and/or activity of the eNOS and thus the NO bioavailability in response to a variety of physiologic and pathophysiologic signals \[[@B48]\].

3. Physiopathological Role of NO in the Vascular System {#sec3}
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The role of NO in the maintenance of vascular homeostasis is well defined and it depends on both eNOS distribution pattern and NO production rate.