MACROPHAGE AND FOAM CELL RELEASE OF MATRIX-BOUND GROWTH-FACTORS - ROLE OF PLASMINOGEN ACTIVATION

We have determined whether macrophage derived-foam cells, a prominent component of the atherosclerotic lesion, express more urokinase-type p lasminogen activator (uPA) and whether their ability to generate plasm in stimulates the.release of matrix-bound growth factors. Steady state levels of uPA mRNA and both membrane and intracellular uPA activities were significantly increased in foam cells. When cultured on cell-der ived matrices containing bound I-125-basic fibroblast growth factor (b FGF), both macrophage and foam cells released intact I-125-bFGF into t heir media. The release of I-125-bFGF by either cell was significantly enhanced in the presence of plasminogen. However, foam cells, which e xpressed more membrane uPA, released more I-125-bFGF than control cell s. The release of matrix-bound bFGF was independent of heparanase acti vity, since neither macrophage nor foam cells degraded (SO4)-S-35-labe led heparan sulfate proteoglycans. In addition, media derived from foa m cells cultured on cell-derived matrices in the presence of plasminog en had increased levels of transforming growth factor (TGF) beta activ ity as compared to cells grown in the absence of plasminogen. In contr ast, plasminogen had no effect on TGF-beta activity recovered in the m edia of foam cells grown on plastic. Moreover, when macrophage were cu ltured on matrices containing bound I-125-TGF-beta, the release of lab eled TGF-beta was increased in the presence of plasminogen. This is th e first demonstration that foam cells can release two important growth regulators, bFGF and TGF-beta, from the extracellular matrix, and pro vides a mechanism by which macrophage and foam cells can stimulate ath erosclerotic lesion development.