101-OR: Cell-Specific Role of Insulin in a Model of Restenosis in Insulin-Sensitive and Insulin-Resistant Conditions

Angioplasty and stenting are widely used in the treatment of atherosclerosis. However, these procedures may fail due to post-angioplasty restenosis, which remains a problem for patients with diabetes. Currently, the vascular role of insulin is unclear. Its role on endothelial cells (EC) is vasculoprotective, whereas its effects on vascular smooth muscle cells (SMC) are mainly mitogenic according to in vitro data. We have previously shown a suppressive effect of insulin treatment on neointimal growth in rodent models of restenosis in insulin sensitive conditions that was abolished in insulin resistant conditions. The objective of this study was to determine the EC-and SMC-specific effects of insulin treatment on neointimal growth in a murine model of restenosis in insulin sensitive and insulin resistant conditions. Mice were generated by crossing insulin receptor (IR) floxed mice with tamoxifen inducible Cre recombinant mice under the control of Cdh5 (vascular endothelial cadherin) or SMMHC (smooth muscle heavy chain) promoters. Mice were fed with a low-fat (LFD) or a high-fat-high-sucrose (HFSD) diet and implanted with insulin pellet (0.U/day) or vehicle (control) prior to femoral artery wire injury. We found that compared to IR-floxed controls, tamoxifen-induced IR^f/f-Cdh5-Cre+ or IR^f/f-SMMHC-Cre+ mice showed a 94% and 80% decrease in IR expression in ECs or SMCs, respectively. In LFD-fed insulin sensitive conditions, insulin decreased neointimal area (NA) and intima-to-media ratio (I/M) in controls (Cdh5 and-SMMHC-floxed and wildtype-Cre+ mice) but not in endothelial and SMC IR deficient mice. In HFSD-fed insulin resistant conditions, insulin had no effect in either controls or endothelial and SMC IR deficient mice. These data demonstrate that insulin action in both ECs and SMCs is required for the anti-restenotic effect of insulin in insulin sensitive conditions, which is abolished but not reversed in insulin resistance even when endothelial IR is deficient.