Macrophages and atherosclerotic plaque stability.

Physical disruption of atheroma frequently causes coronary thrombosis. Ruptured plaques usually have thin fibrous caps overlying a large thrombogenic lipid core rich in lipid-laden macrophages. The biology of plaque monocyte-derived macrophages thus assumes critical importance in understanding plaque instability. Monocyte recruitment involves binding to leukocyte adhesion receptors on the endothelial surface such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Once adherent to the endothelial surface, monocytes enter the intima at sites of lesion predilection. This process probably requires directed migration of the mononuclear cells. A number of chemoattractant molecules, such as the monocyte chemoattractant molecule-1, may participate in signaling this entry of adherent monocytes into the artery wall. Once resident in the arterial intima, monocytes accumulate lipid, via increasingly well characterized receptor-mediated uptake, and transform into macrophage foam cells. These lesional macrophages also acquire other functional properties including production of the potent procoagulant, tissue factor, apolipoprotein E, and an increasing list of cytokines (protein mediators of information and immunity) that may participate importantly in autocrine and paracrine signaling among leukocytes and vascular endothelial and smooth muscle cells. Fatty streaks seldom cause clinical events but may evolve into complicated atheromatous plaques characterized by an accumulation of smooth muscle cells and extracellular matrix and formation of a central core containing extracellular lipid. Death of macrophages, including programmed cell death or apoptosis, probably promotes formation of this thrombogenic lipid pool whose size correlates with plaque instability. Lesion complication often culminates in rupture of the fibrous cap overlying this lipid core. The integrity of the fibrous cap, and thus its resistance to rupture, depends critically on the collagenous extracellular matrix of the plaque's fibrous cap. This aspect of plaque structure in turn depends upon the balance between synthesis and degradation of the macromolecules that comprise the extracellular matrix of the cap, principally interstitial forms of collagen derived from arterial smooth muscle cells. Collagen breakdown, however, appears to depend critically on macrophages. Plaque macrophages express a variety of matrix-degrading enzymes that can contribute to the weakening of the fibrous cap. In this way, macrophages can critically influence aspects of the biology of human atheroma related to lesion stability. We hypothesize that lipid-lowering reduces clinical events, as shown in recent trials, by stabilizing lesions in part by reversing some of the maladaptive functions of macrophages described above.