Endothelium-derived nitric oxide and vascular physiology and pathology

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascula r smooth muscle cells in response to acetylcholine is dependent on the anat omical integrity of the endothelium. Endothelium-derived relaxing factor wa s identified 7 years later as the free radical gas nitric oxide (NO). In en dothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stres s and cell proliferation appear to be, quantitatively, the two major regula tory factors of eNOS gene expression. However, eNOS seems to be mainly regu lated by modulation of its activity. Stimulation of specific receptors to v arious agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine , thrombin) increases eNOS enzymatic activity at least in part through an i ncrease in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although th e precise mechanisms activating the enzyme remain to be elucidated. Phospho rylation and subcellular translocation (from plasmalemmal caveolae to the c ytoskeleton or cytosol) are probably involved in these regulations. Althoug h eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production co uld be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several r isk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Seve ral mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pu lmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and coul d provide insights for new therapies, particularly in hypertension and athe rosclerosis.