Mast cells are present in the arterial intima, the site of atherogenesis. To gain insight into the possible role of mast cells in the formation of the cholesterol-loaded macrophage foam cells typical of both early and late atherosclerotic lesions, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in medium to which low-density lipoproteins (LDL) had been added. Stimulation of the mast cells was found to induce a 50-fold enhancement of LDL uptake by the macrophages, which concomitantly accumulated LDL-derived cholesterol. This process, called the "granule-mediated uptake of LDL", involves the following steps: (i) exocytosis of the cytoplasmic granules of the mast cells, (ii) escape of soluble granule components, such as histamine and a fraction of the granule heparin proteoglycans into the medium, leaving granule remnants consisting of neutral proteases embedded in a heparin proteoglycan matrix, (ii) binding of LDL to binding sites on the glycosaminoglycan side chains of the heparin proteoglycan component of the granule remnants, (iv) proteolytic degradation of the bound LDL by the neutral proteases of the granule remnants, (v) fusion of degraded LDL particles on the surfaces of the granule remnants, and (vi) phagocytosis of the LDL-laden granule remnants by the macrophages. Simultaneously, the soluble heparin proteoglycans, to which no proteolytic enzymes are bound, interact with LDL with formation of insoluble complexes which are also phagocytosed by the macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)