TRANSCRIPTION FACTOR PU.1 MEDIATES INDUCTION OF C-FMS IN VASCULAR SMOOTH-MUSCLE CELLS - A MECHANISM FOR PHENOTYPIC CHANGE TO PHAGOCYTIC-CELLS

The macrophage colony-stimulating factor receptor encoded by the c-fms gene is expressed in vascular intimal smooth muscle cells isolated fr om atherosclerotic lesions. A combination of platelet-derived growth f actor-BE and epidermal growth factor induces stable expression of c:fm s in normal vascular medial smooth muscle cells, The mechanism by whic h these growth factors induce c-fms expression has now been investigat ed in an attempt to gain insight into the events that underlie the phe notypic conversion of vascular smooth muscle cells in atherosclerosis. Deletion analysis of the c-fms promoter revealed that the region incl uding a binding site for transcription factor PU.1 was required for tr anscriptional activity in human aortic medial smooth muscle cells. Mut ation in the PU.1 binding site markedly reduced promoter activity. Nor thern (RNA) blot analysis demonstrated that growth factors induced the expression of PU.1 mRNA in vascular medial smooth muscle cells and th at PU.1 mRNA was expressed in vascular intimal smooth muscle cells, PU .1 antisense oligonucleotides inhibited growth factor-induced c-fms ex pression and foam cell formation. These results suggest that transcrip tion factor PU,I plays an essential role in the phenotypic conversion of vascular smooth muscle cells to macrophagelike cells by mediating t he induction of c-fms.