In pig coronary arteries atherosclerosis developed progressively after an experimental mechanical injury to the endothelium, despite its regeneration. The atherosclerotic process can be considerably accelerated by a high cholesterol diet. In arteries with regenerated endothelium, there is a reduction of endothelium-dependent relaxations mediated by (a) pertussis toxin-sensitive G protein(s). As this includes the response to platelet-derived serotonin, the ability of the regenerated endothelium to prevent abnormal vasoconstrictions (and presumably to feedback on platelet aggregation) in response to aggregating platelets is seriously curtailed. These changes are exacerbated in atherosclerotic arteries. Bioassay studies demonstrate that reduced endothelium-dependent relaxations are due mainly to a reduced release of endothelium-derived relaxing factor. Thus, endothelial dysfunction, in particular the reduced ability to release endothelium-derived relaxing factor, is a key factor in determining the abnormal responsiveness of the atherosclerotic blood vessel wall.