MAST-CELL GRANULE REMNANTS CARRY LDL INTO SMOOTH-MUSCLE CELLS OF THE SYNTHETIC PHENOTYPE AND INDUCE THEIR CONVERSION INTO FOAM CELLS

We report the effect of mast cells on the uptake of LDL by smooth muscle cells (SMCs) and their conversion into foam cells in vitro. The mast cells were stimulated to exocytose their cytoplasmic secretory granules, and the granule remnants formed were recovered from the extracellular fluid and added to cultures of SMCs of either the synthetic or contractile phenotype in LDL-containing medium. In the presence but not in the absence of granule remnants, SMCs of the synthetic phenotype took up LDL with ensuing stimulation of intracellular cholesteryl ester synthesis and cytoplasmic accumulation of neutral lipid droplets. Using methylated LDL (mLDL), a modified species of LDL that binds to granule remnants but not to LDL receptors, we demonstrated that this uptake (leading to foam cell formation) occurred only when LDL was bound to granule remnants. After the addition of colloidal gold-LDL and granule remnants to the incubation system, electron microscopy revealed that within phagosomes of the SMCs there were granule remnants (diameter, 0.5 to 1 mu m) coated with LDL, confirming that LDL had been carried into the cells with the remnants. SMCs of the contractile phenotype were less efficient than their synthetic counterparts at phagocytosing LDL-coated granule remnants and were not converted into foam cells. This difference in the rate of phagocytosis of granule remnants was present even in the absence of LDL, revealing that the more active phagocytosis by SMCs of the synthetic phenotype was not specifically related to uptake of lipids but rather reflected a general phenotype characteristic of these cells. These observations indicate a phagocytic mechanism by which SMCs of the synthetic phenotype are converted into cholesteryl ester-filled foam cells, and they also suggest that degranulation of mast cells plays a role in the development of fatty streak lesions.