Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor.
Since in several vascular diseases abnormal vascular smooth-muscle cell (VSMC) proliferation is often associated with the presence of macrophages, 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 macrophage-colony-stimulating activity was detected in the serum-free supernatant of VSMCs, which could be inhibited by the addition of specific anti-M-CSF antibodies. The presence of M-CSF receptor protein and of M-CSF and M-CSF receptor gene transcripts was demonstrated by immunocytochemistry, using a specific anti-c-Fms antibody and Northern blot analysis respectively. [3H]Thymidine incorporation was measured following the addition to quiescent VSMCs of various dilutions of L929 cell supernatant (as a source of M-CSF) or of recombinant M-CSF. Both exogenous M-CSF and serum-free VSMC conditioned medium promoted DNA synthesis in a concentration-dependent manner, and this effect could be abrogated by the presence of a specific anti-M-CSF antibody. Under similar experimental conditions, L929 cell supernatant modulated proto-oncogene expression, 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 growth 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 and the VSMC level confer to M-CSF a central role in the development of vascular lesions that occurs during atherosclerotic progression.
Herembert
T
T
Université René Descartes and Department of Pharmacology, CNRS URA 1482, CHU Necker, 156 rue de Vaugirard, 75015 Paris, France.
Gogusev
J
J
Zhu
D L
DL
Drueke
T B
TB
Marche
P
P
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D007739:L Cells; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D013917:Thrombin / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic
D000199:Actins; D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D013917:Thrombin; D013936:Thymidine