Risk factors and pathogenesis of atherosclerotic lesion.

Vascular pathological changes exhibit variable features as a result of the functional and morphological differences between blood vessel types . Endothelial dysfunction induces vascular changes associated with an imbalance between vasoactive substances and vessel structure. Various pathological and physiological conditions induce disturbances in the contractility and permeability associated with morphological changes. The abnormal intraendothelial and interendothelial transports of circulating macromolecules may be the first step in the development of atherosclerosis . Atherosclerosis is a major cause of the morbidity and mortality associated with myocardial infarction and cerebral bleeding. Intimal thickening with lipid deposition affects the elastic properties and contributes to the hydrophobic changes that occur in the intima of arteries. The anisotropic elasticity induced by microelastic changes is associated with functional disturbances of the vascular wall. In the atheromatous lesion, infiltrated macrophages, lymphocytes and platelets produce various kinds of cytokines and growth factors . These cytokines and growth factors are synthesized by vascular cells such as the endothelial and smooth muscle cells and induce the inflammatory-fibroproliferative response that is associated with cell proliferation and the production of extracellular matrix( ECM) . Proliferated smooth muscle cells induce local changes in the production of extracellular matrix components, and may contribute to local weakening of the fibrous cap. In the review presented here we discuss the mechanisms underlying the devolopment and fragility of atherosclerosis. 1.The role of endothelial dysfunction in atherosclerosis Normal endothelial cells synthesize prostacyclin , plasminogen activator, factor VIII including the von Willebrand factor and various other components 1 . The endothelium forms a barrier to the passage of blood constituents into the vascular wall and reveals various functional properties(Table 1). Endothelin, which is also found in the endothelium, is a potent vasoconstrictive peptide. ET(endothelin)A receptors predominate in the media of both normal and diseased blood vessels, and ETB receptors have been found on endothelial cells and macrophages . Acetylcholine is known to increase the plasma endothelin concentration of patients with endothelial dysfunction, and is associated with vasoconstriction. Vasoconstrictors acting on aortic smooth muscle cell receptors evoke a depolarization in the endothelial membrane potential . And also increases in ETconverting enzyme-1, ET-1, and its receptor expression play an active role in the pathogenesis of neointimal thickening . Vascular endothelial growth factor (VEGF)and ET-1 have stimulatory interactions on each expression, which may play an important role in concomitant proliferation of endothelial and smooth muscle cells in the vascular wall. On the other hand, nitric oxide(NO)formation by endothelial cells is enhanced by a variety of physical and chemical stimuli, among which the most important factor may be flow-induced shear stress. The inJ Nippon Med Sch 1999;66(6)