Abstract 13492: Increasing Endothelial Insulin Sensitivity Rescues Vascular Function and Repair in Systemic Insulin Resistance by Restoring Nitric Oxide Bioavailability and Improving Endothelial Cell Migration

Abstract

Introduction: Insulin resistance is independently associated with vascular disease. Insulin receptor haploinsufficient (IRKO) mice are hypertensive and exhibit endothelial dysfunction and impaired vascular repair despite normal glucoregulation. We hypothesise that endothelial insulin signalling is crucial for vascular function and that selectively restoring endothelial cell (EC) insulin signalling may rescue these vascular derangements. Methods: Transgenic mice with Tie-2-driven human IR expression in the endothelium (HIRECO) were bred with IRKO, providing HIRECOxIRKO (HxI) offspring. Metabolic assessment included glucose and insulin tolerance tests, ELISA for plasma insulin concentration and non-invasive blood pressure measurement. Femoral artery injury was performed with angioplasty wires; repair was quantified in Evans Blue-perfused vessels at day 4. Circulating endothelial progenitor cells (EPC) were counted using FACS and cultured from blood. Explanted aortic rings were exposed to phenylephrine (PE) before and after incubation with the NOS inhibitor L-NMMA in organ baths to assess vasomotor function. Boyden chamber assays were used to assess migration of cultured lung ECs to VEGF. Data are expressed as mean(SE) and compared using t-tests;*=p<0.05. Results: HxI and IRKO had similar glucocompetence and basal insulin [0.8(0.1)ng/mL vs 0.7(0.2);p=0.8]. Systolic BP was lower in HxI [97(2)mmHg vs 106(3)*]. Vascular repair was improved in HxI [57(4)% vs 46(2)%*]. There was no recovery in EPC numbers by FACS [99(10) vs 105(15);p=0.74], nor in culture [0.4(0.1)/HPF vs 0.4(0.2);p=0.99]. HxI aortic rings showed less PE-induced constriction than IRKO [EC50 8.9(0.8)x10 7 nM vs 6.3(0.9)x10 7 *], with greater NO bioavailability [Post-L-NMMA PE EC50 4.1(0.8)x10 7 nM vs IRKO 6.1(1.8)x10 7 *]. ECs from HxI showed greater net migration to VEGF [6.3(1.3) vs 1.9(1.2)*]. Conclusion: HIRECOxIRKO show rescue of vascular function despite global insulin resistance. This is not associated with improved glucoregulation or EPC abundance; rather, it may relate to increased NO availability and enhanced EC migration. Our data support endothelial insulin sensitisation as a potential therapeutic target for vascular dysfunction in insulin resistance.