Macrophages and arterial smooth muscle cells comprise the cellular components of the atherosclerotic plaque. The vessel wall accumulation of macrophages occurs by a process of increased circulating monocyte migration into the vessel wall.In these studies it is demonstrated that human macrophages and arterial smooth muscle cells in culture secrete potent chemotactic factors for freshly isolated human monocytes. In contrast, human fibroblast-conditioned medium has no chemotactic activity. The effect of macrophage-conditioned medium is a function of macrophage differentiation and can be potentiated by macrophage activation. These results suggest that secretory products of human macrophages and arterial smooth muscle cells may be important stimuli for increased monocyte migration into the vessel wall in vivo.Atherosclerotic plaques are characterized by vascular wall collections of lipid-laden cells referred to as "foam cells." There is now substantial evidence that these cells originate from arterial smooth muscle cells and from monocyte-derived macrophages (1-5). Intimal accumulation of smooth muscle cells occurs as a result of cell division (5, 6), which may be induced by locally active mitogens such as those released by platelets (7), macrophages (8), or endothelial cells (9). Intimal accumulation of macrophages probably results from the migration of blood-borne monocytes into the developing plaque (10), but little is known of the factors that might induce the migration of monocytes into the vascular wall. We now report that conditioned media from cultured human macrophages and arterial smooth muscle cells are chemotactic for freshly isolated human monocytes. These results indicate that cells that are present in the nascent plaque can secrete factors that, if present in vivo, could mobilize monocytes into the vascular wall, thereby promoting growth of the lesion. MATERIALS AND METHODSCell Culture. Human monocytes were prepared from human blood by counterflow centrifugation as described (11 microscopy (12). Cultured human skin fibroblasts were grown from skin biopsies obtained from the anterior thighs of normal volunteers as described (13). Arterial smooth muscle cells and fibroblasts were grown in modified Dulbecco-Vogt medium containing 10% pooled human serum. Cells from the third or greater subculture were allowed to reach near confluence in 35-mm dishes before collection of conditioned media.Prior to the collection of conditioned medium, arterial smooth muscle cells, macrophages, or fibroblasts were washed three times with RPMI 1640 medium and were then incubated in medium alone or in medium containing 0.2% bovine serum albumin. After a 24-hr incubation, media were collected, spun, and frozen at -200C until used in the chemotaxis assay. Unless otherwise specified, macrophage-conditioned medium was collected from day 5-6 cultures and arterial smooth muscle celland fibroblast-conditioned media were collected when cells reached near confluence.For experiments testing the effect of macrophage stimulation...
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