TEMPORAL EXPRESSION OF C-FOS MESSENGER-RNA FOLLOWING BALLOON INJURY IN THE RAT COMMON CAROTID-ARTERY

Objective: Restenosis is a common problem which limits the effectivene ss of percutaneous transluminal coronary angioplasty (PTCA). The cellu lar mechanisms of restenosis appear to involve smooth muscle cell (SMC ) migration to the neointima in response to mitogens and growth factor s, resulting in proliferation and deposition of cells in the lumen of the vessel. An antibody directed against PDGF attenuates this response in the rat. Thus, signaling cascades induced by growth factors includ ing PDGF may be important targets for therapeutic intervention. Method s; Since a number of growth factors activate c-fos via the p21-ras sig naling pathway, we examined c-fos expression in a time course experime nt involving restenotic lesions in rat carotid arteries. Sections of a rteries collected at 1, 3, 7, 14 and 28 days following balloon injury were hybridized using a fluorescein-labeled RNA probe to c-fos. Immuno histochemistry was performed with antibodies to proliferating cell nuc lear antigen (PCNA) and a-sme actin to characterize cellular constitue nts of the neointima, and detect any correlation between fos expressio n and PCNA localization. Results: Expression of c-fos was low at day 1 . By day 3, the media and adventitia were positively stained. At days 7 and 14, most cells in the neointima were labeled. By day 28, c-fos w as expressed mainly in scattered cells along the luminal surface. Cont rol sections revealed little labeling and confirmed specific staining by the antisense strand. PCNA localization and c-fos expression were s imilar at days 1, 3, 7 and 28, but at day 14 c-fos was expressed throu ghout the lesion, with PCNA. localized mainly along the luminal edge. The majority of the cells making up the neointima stained rather inten sely for ol-sme actin, identifying them as SMCs. Conclusions: Results of these experiments indicate that, while c-fos expression correlates with lesion formation, it may be associated with a cellular process di stinct from proliferation in this model.