The endothelium in health and disease.

The early observations of an apparent anomalous action of acetylcholine on the regulation of vascular tone in vivo and in vitro were found to be a reflection of the intactness of the endothelium in vivo. An intact endothelium mediates relaxation of smooth muscle in response to acetylcholine, whereas endothelium-denuded blood vessels exposed to this agonist often exhibit vasoconstriction. The vasodilation is mediated by the actions of the endothelium-derived relaxing factors nitric oxide and prostacyclin. In addition, endothelial cells release endothelium-derived hyperpolarizing factor, which regulates potassium-channel opening in vascular smooth muscle. The chemical nature of this molecule remains to be elucidated. Many of the physiologic stimulants for endothelium-derived relaxing factor production are released by aggregating platelets, and the significance of the endothelium's vasoprotective role becomes apparent when the mechanisms and consequences of platelet agglutination are studied. Damage to the endothelium, however minor, results in the loss of this protective function and is associated with an impaired response to serotonin of G-protein coupled receptors. In the presence of risk factors such as elevated serum cholesterol, the consequences of an impaired endothelial function are greatly enhanced. Age-related changes in endothelial responsiveness may account for the prevalence of cardiovascular disease in human beings over the age of 30 years.