CONTROL OF VASCULAR SMOOTH-MUSCLE CELL-GROWTH BY MACROPHAGE-COLONY-STIMULATING FACTOR

Since in several vascular diseases abnormal vascular smooth-muscle cel l (VSMC) proliferation is often associated with the presence of macrop hages, we examined whether macrophage-colony-stimulating factor (M-CSF ) might play a role in the control of VSMC growth. VSMCs were isolated from rat aorta and maintained in culture. Using a bioassay, a macroph age-colony-stimulating activity was detected in the serum-free superna tant of VSMCs, which could be inhibited by the addition of specific an ti-M-CSF antibodies. The presence of M-CSF receptor protein and of M-C SF and M-CSF receptor gene transcripts was demonstrated by immunocytoc hemistry, using a specific anti-c-Fms antibody and Northern blot analy sis respectively. [H-3]Thymidine incorporation was measured following the addition to quiescent VSMCs of various dilutions of L929 cell supe rnatant (as a source of M-CSF) or of recombinant M-CSF. Both exogenous M-CSF and serum-free VSMC conditioned medium promoted DNA synthesis i n a concentration-dependent manner, and this effect could be abrogated by the presence of a specific anti-M-CSF antibody. Under similar expe rimental conditions, L929 cell supernatant modulated proto-oncogene ex pression, as assessed by Northern blot analysis of c-fos, c-myc, egr-1 and junB. It was further demonstrated that M-CSF could act in synergy with thrombin, platelet-derived growth factor or basic fibroblast gro wth factor in promoting VSMC DNA synthesis. These results support the hypothesis that M-CSF affects the growth of cultured rat VSMCs through paracrine/autocrine mechanisms. Its effects at both the macrophage an d the VSMC level confer to M-CSF a central role in the development of vascular lesions that occurs during atherosclerotic progression.