IGF-I increases bFGF-induced mitogenesis and upregulates FGFR-1 in rabbit vascular smooth muscle cells.
Insulin-like growth factor-I (IGF-I) and basic fibroblast growth factor (bFGF) have both been implicated in the abnormal proliferation of vascular smooth muscle cells (VSMC) that occurs after injury to the arterial wall in vivo. We have investigated the effects of these growth factors on proliferation of rabbit aortic smooth muscle cells (RASMC) in vitro. IGF-I, in contrast to bFGF, is a weak mitogen for RASMC. However, 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 after 16 h, activity peaked at 24 h, and a synergistic response with IGF-I was not observed before 24 h. Northern blot analysis demonstrated that IGF-I (10 ng/ml) could selectively upregulate fibroblast growth factor receptor-1 (FGFR-1) mRNA 4.0 +/- 0.24-fold (P < 0.001) without a significant effect on FGFR-2, and this induction in FGFR-1 mRNA occurs in 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 demonstrated by Western blotting, and this upregulation occurs before the peak in DNA synthesis. These results suggest that IGF-I may be capable of increasing the responsiveness of VSMC to bFGF through modulation of FGFR-1.
Reape
T J
TJ
Department of Medicine, United Medical School, St. Thomas's Hospital, London, United Kingdom.
Kanczler
J M
JM
Ward
J P
JP
Thomas
C R
CR
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1