The role of vascular smooth muscle cells on the pathogenesis of atherosclerosis

Abstract

Atherosclerosis is the leading cause of death and disability. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses. The earliest changes that precede the formation of lesions of atherosclerosis take place in the endothelium (EC), with resultant endothelial dysfunction. The EC-induced injury can result in increased lipid permeability, macrophage recruitment, formation of foam cells, and recruitment of T-lymphocytes and platelet. After intimal injury, different cell types,including ECs, platelets, and inflammatory cells release mediators, such as growth factors and cytokines that induce multiple effects including phenotype change of vascular smooth muscle cells (VSMC) from the quiescent "contractile" phenotype state to the active "synthetic" state, that can migrate and proliferate from media to the intima. The inflammatory response simulates migration and proliferation of VSMC that become intermixed with the area of inflammation to form an intermediate lesion. These responses continue uninhibited and is accompanied by accumulation of new extra cellular matrix (ECM). The migratory and proliferative activities of VSMC are regulated by growth promoters such as platelet derived growth factors (PGF), endothelin-1 (ET-1), thrombin, fibroblast growth factor (FGF), interleukin-1 (IL-1) and inhibitors such as, heparin sulfates , nitric oxide (NO), transforming growth factor (TGF)-beta. The matrix metallo proteinases (MMPs) could also participate in the process of VSMC migration. MMPs could catalyze and remove the basement membrane around VSMC and facilitate contacts with the interstitial matrix. This could promote a change from quiescent, contractile VSMC to cells capable of migrating and proliferating to mediate repair. The VSMC regulation is a very complex process, VSMC are stimulated to proliferate and migrate by some kind of cytokines, growth factors, angiotensin II (Ang-II). Together with apoptosis, proliferation and migration of VSMC are vital to the pathogenesis of atherosclerosis and plaque rupture. Rupture of the plaque is associated with increased fibrous cap macrophage, increased VSMC apoptosis, and reduced fibrous cap VSMC. VSMC are the only cells with plaques capable of synthesizing structurally important collagen isoforms, and the apoptosis of VSMC might promote plaque rupture.