Which endothelium-derived factors are really important in humans?

The endothelium plays a primary role in the local control of vascular function and structure, mainly by the production and release of NO, a potent vasodilator that also inhibits all the mechanisms involved in the pathogenesis of atherosclerosis, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. Cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals that reduce NO availability and the release of contracting factors, including prostanoids and endothelin-1. In humans, endothelium-dependent relaxation can be assessed by tests that explore vascular reactivity. Besides the degree of vasodilation, which represents a crude estimate of endothelial function, the utilization of a complex experimental design, requiring the administration of specific agonists and antagonists, allows detailed exploration of the mediators and mechanisms involved in endothelium-dependent vasodilation. At present, the degree of endothelium-dependent vasodilation (evoked by receptor-operated agonists or the application of mechanical forces) is considered an independent predictor of cardiovascular events. In contrast, scant information is available concerning the clinical relevance of different mediators involved in endothelial function. Further studies are needed in the future to assess the specific impact of different endothelial responses on the clinical outcome in patients with cardiovascular risk factors and disease.