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Endothelial cells control vascular tone by releasing nitric oxide (NO) produced by endothelial NO synthase. The activity of endothelial NO synthase is modulated by the calcium concentration and by post-translational modifications (eg, phosphorylation). When NO reaches vascular smooth muscle, soluble guanylyl cyclase is its primary target producing cGMP. NO production is stimulated by circulating substances (eg, catecholamines), platelet products (eg, serotonin), autacoids formed in (eg, bradykinin) or near (eg, adiponectin) the vascular wall and physical factors (eg, shear stress). NO dysfunction can be caused, alone or in combination, by abnormal coupling of endothelial cell membrane receptors, insufficient supply of substrate (l-arginine) or cofactors (tetrahydrobiopterin), endogenous inhibitors (asymmetrical dimethyl arginine), reduced expression/presence/dimerization of endothelial NO synthase, inhibition of …