Hyperlipidemia and Endothelial Vasodilator Dysfunction: The Pathogenetic Link to Myocardial Ischemia

Abstract

The endothelium is a crucial vascular structure, not only because of its strategically important barrier function as the interface between the flowing blood and the vascular wall, but also because it is a source of a variety of mediators regulating vascular growth, platelet function and coagulation. In addition, the endothelium plays a critical role in the control of vasomotor tone by synthesizing and metabolizing vasoactive substances including an endothelium-derived hyperpolarizing factor, prostacyclin, and, most notably, endothelium derived relaxing factor (EDRF), which has been identified as nitric oxide (NO) or a related compound [1]. NO, which is formed from L-arginine by the action of a constitutive form of the enzyme nitric oxide synthase [2], has been shown to inhibit platelet aggregation and adhesion, to modulate smooth muscle cell proliferation, to attenuate the generation of endothelin, and to modulate leukocyte and monocyte adhesion to the endothelium, all of which are cardinal features in the pathogenesis of atherosclerosis. Thus, in addition to the vasorelaxing effects of NO caused by stimulating guanylate cyclase to increase cyclic GMP levels in the vascular smooth muscle cell layer, NO appears to exert potent antiatherosclerotic functions.