IGF-I INCREASES BFGF-INDUCED MITOGENESIS AND UP-REGULATES FGFR-1 IN RABBIT VASCULAR SMOOTH-MUSCLE CELLS

Insulin-like growth factor-I (IGF-I) and basic fibroblast growth facto r (bFGF) have both been implicated in the abnormal proliferation of va scular smooth muscle cells (VSMC) that occurs after injury to the arte rial wall in vivo. We have investigated the effects of these growth fa ctors on proliferation of rabbit aortic smooth muscle cells (RASMC) in vitro. IGF-I, in contrast to bFGF, is a weak mitogen for RASMC. Howev er, when IGF-I (10 ng/ml) was added in combination with bFGF for 24 h, the effect of the two growth factors on DNA synthesis was synergistic at all. concentrations tested (P < 0.001 compared with summed values of bFGF alone plus IGF-I alone), and this synergy was also observed at the level of RASMC proliferation (P < 0.001). Time-course experiments indicated that although bFGF was able to stimulate DNA synthesis afte r 16 h, activity peaked at 24 h, and a synergistic response with IGF-I was not observed before 24 h. Northern blot analysis demonstrated tha t TGF-I (10 ng/ml) could selectively upregulate fibroblast growth fact or receptor-1 (FGFR-1) mRNA 4.0 +/- 0.24-fold (P < 0.001) without a si gnificant effect on FGFR-2, and this induction in FGFR-1 mRNA occurs i n a time- and dose-dependent manner. In addition, IGF-I increases FGFR -1 protein levels in RASMC 2.7 +/- 0.12-fold (P < 0.01), as demonstrat ed by Western blotting, and this upregulation occurs before the peak i n DNA synthesis. These results suggest that IGF-I may be capable of in creasing the responsiveness of VSMC to bFGF through modulation of FGFR -1.