453-P: Cell-Specific Role of Insulin in an In Vivo Model of Restenosis

The effects of insulin on the vasculature remains a hotly debated and controversial topic. Its role on endothelial cells (ECs) is thought to be vasculoprotective, whereas its effects on vascular smooth muscle cells (SMCs) are mainly mitogenic according to in vitro data. We have previously demonstrated a suppressive effect of insulin treatment on neointimal growth in rodent models of restenosis under conditions of normal insulin sensitivity that was abolished in insulin resistant conditions. The objective of this study was to determine the endothelial-and SMC-specific effects of insulin treatment on neointimal growth in a murine model of restenosis. Mice were generated by crossing loxP-flanked insulin receptor (IR) mice with mice overexpressing tamoxifen-inducible Cre recombinase under the control of Tie2 (endothelial-specific receptor tyrosine kinase) or SMMHC (smooth muscle myosin heavy chain) promoters. Mice were fed with standard chow and implanted with insulin pellet (0.1 U/day) or sham (control) three days prior to undergoing femoral artery wire injury. Lastly, femoral arteries were collected for morphological analysis 28 days after wire injury. Tamoxifen-induced Tie2-Cre+ mice showed decreased IR expression in ECs compared with Tie2-Cre-, with no change in IR expression in SMCs. Neointimal area in Tie2-Cre- mice was reduced following insulin treatment, whereas it was unaffected in Tie2-Cre+ mice. Similarly, tamoxifen-induced SMMHC-Cre+ mice showed a reduction in IR expression in SMCs, but not in the ECs, compared to SMMHC-Cre- mice. In SMMHC-Cre- mice, neointimal area was decreased with insulin treatment; however, insulin surprisingly failed to have the same effects in SMMHC-Cre+ mice. These data demonstrate that insulin action in both ECs and SMCs is required for the antirestenotic effect of insulin in insulin sensitive conditions.