Insulin like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors

PURPOSE: Vascular smooth muscle cell (VSMC) proliferation is an early event in the pathogenesis of atherosclerosis. Insulin and glucose are known to s timulate the growth of VSMC, Cell membrane receptors play an important role in the proliferation of VSMC in response to growth factors. Insulin and in sulin-like growth factor-1 (IGF-1) have demonstrated a cross reactivity for receptor binding and function. By using monoclonal antibodies directed aga inst insulin (IRA) and IGF-1 (IGF-IRA) receptors, we attempt to further del ineate the mechanism for the proliferation of VSMC in response to insulin a nd glucose. METHODS: Human infragenicular VSMC isolated from diabetic patients undergoi ng below-knee amputations were used. Cells from passages 3 to 6 were grown in serum-free media with a glucose concentrations of 0.1% or 0.2%, both wit h and without insulin (100 ng/mL). The baseline cell density was 4,635 +/- 329 cells/mL, IRA or IGF-1RA was added to the media, with the control group receiving neither antibody. Cells were grown in 5% CO2 at 37 degrees C for 6 days. Analysis of variance was used for statistical analysis, with P <0. 05 considered significant. In addition, DNA synthesis was measured using th ymidine incorporation assays in the same groups of cells receiving IRA, IGF -IRA, and no antibody. RESULTS: IGF-1RA prevented the proliferation of VSMC in response to insulin and glucose, while IRA had no effect on cell growth. There was no signific ant growth when IGF-1RA was added to the media, while the control group and the group receiving IRA demonstrated significant growth compared with the baseline concentration of 4,635 +/- 329 cells/mL at all concentrations of i nsulin and glucose. [H-3]thymidine incorporation assays confirmed the cell count results. CONCLUSIONS: These results suggest that the mitogenic effects of insulin an d glucose on infragenicular VSMC are due to stimulation of the IGF-I recept or. VSMC antiproliferative strategies employing receptor blockade should be directed against the IGF-1 receptor, not the insulin receptor. Am J Surg. 1999;178:156-161. (C) 1999 by Excerpta Medica, Inc.