CELLULAR MECHANISMS OF ATHEROGENESIS

The study of vascular cell function and the interactions of endothelial cells (EC), smooth muscle cells (SMC), and monocyte-derived macrophages has expanded greatly during the past 20 years, and the resultant information has reformed our views on the genesis of atherosclerotic plaque. The concept of an activated or injured endothelium that exhibits properties distinct from healthy adult endothelium is now well accepted. Activated EC may exhibit proatherogenic behavior, including increased leukocyte adhesivity, procoagulant activity, and SMC mitogen production. Thrombin, a coagulation-system protease, may serve as a physiologic activator of EC. Thrombin at sites of vascular injury may stimulate diverse functions, including increased expression of monocyte adhesion proteins and platelet-derived growth factor (PDGF). The monocyte-derived macrophage has been implicated as a participant in several aspects of atherosclerotic plaque development. The attachment of monocytes to EC is the initial event in the interaction of these cells with the vessel wall. Distinctly focal adhesion of monocytes to EC of large vessels is one of the earliest documented events in experimentally induced atherosclerosis and, thus, regulation of this process may be critical to the development of the disease. Intimal proliferation of SMC is another hallmark of the atherosclerotic lesion. Platelet-derived growth factor is both a chemoattractant and mitogen for SMC. Therefore, if EC secrete PDGF abluminally, both the migration of SMC into the intima and subsequent proliferation will be stimulated. Immunocytochemistry and in-situ hybridization have verified that vascular EC express PDGF mRNA and protein in vivo under certain conditions. The intracellular pathways employed by thrombin to stimulate PDGF production by EC are becoming defined, and differences have been found in the signals employed in this process v induced leukocyte adhesion. Therefore, under specific environmental conditions, thrombin may induce both PDGF and monocyte adhesion proteins whereas, in other situations, only one of the two responses is induced. Thus, specific paracrine functions of the EC may be activated temporally to catalyze such processes as wound-healing, inflammation, vascular restenosis, and atherosclerosis.