THE CELL BIOLOGY OF ATHEROSCLEROSIS - NEW DEVELOPMENTS

In the development of atherosclerotic lesions, three basic processes o ccur: 1) invasion of the artery wall by leucocytes, particularly monoc ytes and T-lymphocytes; 2) smooth muscle phenotypic modulation, prolif eration, and synthesis of extracellular matrix; and 3) intracellular ( macrophage and smooth muscle) lipoprotein uptake and lipid accumulatio n. Invasion of the vessel wall by leucocytes is mediated through the e xpression of adhesion molecules on both leucocytes and the endothelium making them 'sticky'. The adhesion molecules are induced by high seru m cholesterol levels or complement fragments. Leucocytes which have ad hered to the endothelium are chemo-attracted into the vessel wall by c ytokines produced by early arriving leucocytes or by low density lipop rotein which has passively passed into the wall, in the process being trapped and oxidised. The oxidised low density lipoprotein is taken up by scavenger receptors (which are not subject to down-regulation) on both macrophages and smooth muscle cells. The overaccumulation of lipi d is toxic to the cells and they die contributing to the central necro tic core. The macrophages and T-lymphocytes produce substances which i nduce smooth muscle cells of the artery wall to change from a 'contrac tile' (high volume fraction of myofilaments [V(v)myo]) to a 'synthetic ' (low V(v)myo) phenotype. In this altered state they respond to growt h factors released from macrophages, platelets, regenerating endotheli al cells and smooth muscle cells; produce large amounts of matrix; exp ress lipoprotein scavenger receptors; express adhesion molecules for l eucocytes; and express HLA-DR following exposure to the T-lymphocyte p roduct, IFN-delta, suggesting that they can become involved in a gener alised immune reaction.