Abstract 17875: Endothelial Cell Insulin Sensitivity and Nitric Oxide Bioavailability Are Regulated by Insulin-Like Growth Factor-1 and Insulin Receptor Levels
The growth promoting hormone Insulin-like growth factor-1 (IGF-1) similar to insulin may be an important regulator of nitric oxide (NO) bioavailability. We have previously reported in two murine models of reduced IGF-1 receptor (global hemizygous knockout (IGFRKO) and endothelial cell specific IGF-1R knockout (ECIGFRKO)) evidence of increased basal NO production in the vasculature, with augmentation of this increase relative to decreasing IGF-1R number (WT v ECIGFRKO hemizygotes p=0.01, WT vs ECIGFRKO homozygotes p = 0.001). Furthermore, by decreasing IGF-1R numbers in the insulin resistant hemizygous insulin receptor knockout (IRKO) model (IRKO x IGFRKO) insulin sensitivity in the vasculature can be restored. In this study, we have investigated further these receptor interactions with the generation of a mouse overexpressing the human IGF-1R specifically in the endothelium under control of the Tie-2 promoter-enhancer (hIGFREO) and by targeted knockdown of the IGF-1R in human endothelial cells. Glucose and insulin tolerance testing showed no difference between hIGFREO mice and wild-type (WT) littermates. Vascular function was assessed using thoracic aortic rings in an organ bath. hIGFREO mice were hypercontractile to phenylepherine (PE) compared to WT (Emax hIGFREO = 0.91 ± 0.045; WT = 0.62 ± 0.045, p=0.0036) with decreased response to LNMMA (Emax hIGFREO = 47.70±9.87; WT = 106.1± 30.10g, p=0.048) indicative of reduced NO bioavailability. To further examine the role of IGF-1R in regulating eNOS activity HUVECs were transfected with IGF1R-siRNA and showed increased basal and Insulin-mediated eNOS phosphorylation in the presence of Insulin (Ins: 164±4.9% vs. siRNA+Ins: 192±0.7%, p<0.05). eNOS activity (L-arginine, L-citrulline assay) was enhanced upon transfection with IGF1R-siRNA (Scrambled siRNA: 95.7±13.7% vs IGF1R-siRNA: 188.7±48.3%, p<0.05). These data demonstrate that increased numbers of IGF-1R specifically in the endothelium leads to reduced NO bioavailability. Complementary siRNA studies confirm reducing IGF-1R numbers enhance NO bioavailability. Manipulation of IGF-1R numbers may represent a novel therapeutic strategy by which to modify vascular NO bioavailability.
- © 2010 by American Heart Association, Inc.