The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator.

The cardiovascular system is regulated by the central mechanisms, hormones and local vascular mediators. Anatomically, the endothelium lies between smooth muscle cells of the blood vessel wall and the circulating platelets and monocytes. In response to mechanical and humoral signals, endothelial cells release mediators modulating contraction and proliferation of vascular smooth muscle, platelet adhesion and aggregation, coagulation and monocyte adhesion. Nitric oxide (NO), prostacyclin and a putative hyperpolarizing factor mediate relaxation. NO also inhibits smooth muscle migration and proliferation and, together with prostacyclin, platelet adhesion and aggregation. Endothelin-1, thromboxane A2 and prostaglandin H2 are endothelium-derived contracting factors. In contrast to thromboxane A2 and prostaglandin H2 which activate platelets, endothelin-1 has no direct platelet effects, but has proliferative properties in vascular smooth muscle. Under physiological conditions, the endothelium exerts vascular protective effects as it prevents adhesion of blood cells, dilates the vasculature and inhibits vascular smooth muscle proliferation. In disease states, however, endothelial dysfunction mediates vasoconstriction, adhesion of platelets and monocytes and proliferation of vascular smooth muscle cells, all events known to contribute to atherosclerotic vascular disease.