Molecular and cellular concepts in atherosclerosis

Atherosclerosis is a complex disease of uncertain cause. Its pathobiology is believed to represent an abnormal expression of the processes of vascular healing. Etiologic models derive from a 'response to injury' paradigm and can be divided into three separate disease stages: endothelial dysfunction, smooth muscle proliferation and architectural disruption. The initiating event of endothelial dysfunction is unknown, but is believed to be related to low-density lipoproteins and/or their oxidized derivatives. Endothelial injury is signalled to the smooth muscle cells of the media by three routes: direct cell-cell interaction, secretion of soluble growth factors and monocyte-derived cytokines. Monocytes are recruited by the endothelium and invade the subintimal space by a complex interaction of a variety of adhesion proteins and receptors on both cell types. Smooth muscle cell proliferation is initiated by a change in phenotype expression from 'contractile' to 'synthetic' resulting from the binding of fibronectin to specific integrin receptors. Three functionally distinct activities may represent separate subtypes of the 'synthetic phenotype': migration from the media to the intima, increased proliferation and inappropriate extracellular matrix synthesis. The loss of normal regulatory control and anchorage independence of proliferation suggest a relationship to oncogenic transformation. Both migration and proliferation result from the binding of platelet-derived growth factor-like factors to smooth muscle cell receptors, which initiates a cascade of intracellular molecular events leading either to cytoskeletal locomotory restructuring or cell cycle activation. Both pathways also appear to be coregulated by integrin receptors and both depend upon phosphorylation of cell membrane, cytosolic and nuclear regulatory proteins. Clinical expression of atherosclerosis may follow sudden loss of architectural integrity of the intimal plaque by three different mechanisms: plaque fissuring, intraluminal plaque rupture or intramural hemorrhage related to abnormal vessel wall stress and/or biochemistry.