The Atherosclerosis Time-Line and the Role of the Endothelium

Atherosclerosis remains a major cause of morbidity and mortality worldwide. Conventional risk factors do not completely account for the development of atherosclerosis and its complications. Accumulating data suggest that endothelial dysfunction has independent prognostic implications. It has been implicated in the initiation of atherosclerosis, the precipitation of acute ischaemia, and the determination of the extent of injury following such complications. Atherosclerosis develops as a consequence of lipid accumulation in the vessel wall, a co-existent inflammatory response and proliferation of smooth muscle cells; endothelial dysfunction can be added to this pathogenic triad. The endothelium regulates numerous blood vessel functions, including vascular tone, cell adhesiveness, and coagulation through the production of mediators. The best characterized of these are the vasodilators, nitric oxide (NO), prostacyclin, and endothelium derived hyperpolarising factor (EDHF), and the vasoconstrictors thromboxane and endothelin. Endothelial dysfunction may encourage the adhesion and transmigration of monocytes and platelets to initiate and promote atherosclerosis. In addition, endothelial dysfunction may precipitate the acute complications of atherosclerosis through vasospasm and thrombosis, and may be a determinant of the transition from stable chronic atherosclerosis, to the development of acute coronary syndromes. Understanding of the biology of the endothelium in atherosclerosis may lead to novel therapies that will retard its progression, and reduce the incidence or consequences of acute complications.