Abstract 13829: Endothelial Insulin Sensitisation Enhances Vascular Repair in Systemic Insulin Resistance and Improves Endothelial Function by Restoring Nitric Oxide Bioavailability
Objectives: Insulin resistance is independently associated with vascular disease. Mice with heterozygous insulin receptor (IR) knock out (IRKO) are non-diabetic, yet exhibit hypertension, endothelial dysfunction and impaired vascular repair, with reduced endothelial progenitor cell (EPC) number/function. We hypothesise that intact endothelial insulin signalling is crucial for vascular function and that its selective restoration may rescue the vascular derangements seen in systemic insulin resistance.
Methods: We generated transgenic mice with Tie-2-driven human IR expression in endothelial cells (HIRECO). These, bred with IRKO, provide HIRECOxIRKO offspring, which were compared with IRKO. Glucocompetence was assessed using glucose- and insulin-tolerance tests and ELISA for plasma insulin concentration. Femoral artery injury was performed using angioplasty guide wires; vessels were excised at day 4 to quantify repair using Evans Blue dye. Circulating progenitor cells (CPC) were counted using FACS and cultured blood-derived EPCs counted using DiI/lectin stain. Finally, aortic rings were exposed to incremental acetylcholine and phenylephrine (PE) before and after incubation with the NOS inhibitor L-NMMA in organ baths to assess vasomotor function. Data are expressed as mean (SE) and compared using t-tests; *=p<0.05.
Results: HIRECOxIRKO and IRKO showed similar glucocompetence and insulin levels [0.8(0.1)ng/mL vs 0.7(0.2);p=0.8] but lower systolic BP [97(2)mmHg vs 106(3)*]. Vascular re-endothelialisation improved in HIRECOxIRKO [57(4)% vs 46(2)%*]. There was no recovery in peripheral CPC [99(10) vs 105(15);p=0.7], nor cultured EPC number [0.4(0.1)/HPF vs 0.4(0.2);p=0.99]. HIRECOxIRKO aortic rings displayed significantly less PE-induced constriction than IRKO [EC50 8.9(0.8)x107nM vs 6.3(0.9)x107nM*] and showed greater NO bioavailability [Post-L-NMMA PE EC50 4.1(0.8)x107nM vs IRKO 6.1(1.8)x107nM*].
Conclusion: HIRECOxIRKO show improved BP, endothelial function, NO bioavailability and vascular repair in the setting of global insulin resistance. This is not related to glucoregulation or EPC abundance. Endothelial insulin sensitisation may be a therapeutic target for vascular dysfunction in insulin resistance.
Author Disclosures: A. Sengupta: None. H. Viswambharan: None. N. Yuldasheva: None. B. Mercer: None. S. Galloway: None. N. Ali: None. A. Walker: None. A. Aziz: None. M. Gage: None. A. Skromna: None. S. Wheatcroft: None. M. Kearney: None. R. Cubbon: None.
- © 2014 by American Heart Association, Inc.