Abstract 16125: Novel Role for Insulin-Like Growth Factor-1 Receptors (Igf-1r) in Endothelial Function and Repair: Studies in an Endothelial Igf-1r Overexpressing Transgenic Model
Endothelium-derived nitric oxide (NO) is a critical regulator of vascular homeostasis, repair and regeneration. We recently demonstrated that decreasing the proportion of insulin resistant hybrid receptors by reducing insulin-like growth factor-1 receptor (IGF-1R) numbers in the endothelium enhances NO bioavailability and increases endothelial cell (EC) insulin sensitivity (Diabetes, in press, May 2011). To examine the effect of increasing IGF-1R in EC we generated transgenic mice overexpressing the human IGF-1R in EC (human IGF-1R endothelium overexpressing mice (hIGFREO)). Increased endothelial IGF-1R numbers had no effect on glucose tolerance or insulin sensitivity in hIGFREO mice compared to wild-type (wt) littermates and fasting plasma glucose, insulin and IGF-1 levels were similar. Aortae from hIGFREO mice were hypercontractile to phenylephrine (PE) (Emax wt = 0.62 ± 0.045 v hIGFREO = 0.91 ± 0.045, p=0.036) and had blunted constrictor responses to LNMMA (Emax wt = 106.1 ± 30.10 v hIGFREO = 47.7 ± 9.87, p=0.048) indicating reduced basal NO bioavailability. EC from hIGFREO had reduced insulin stimulated NO release (wt = 4500 ± 1000 v hIGFREO = 1500 ± 700, p<0.05), determined by DAF-FM fluorescence, and reduced insulin stimulated eNOS activation (wt = 170% ± 25 v hIGFREO 58% ± 3, p<0.04), measured by conversion of L-arginine to L-citrulline. Consistent with reduced NO bioavailability the NO dependent process of angiogenesis assessed in a number of complementary assays was significantly attenuated in hIGFREO mice (mean length of angiogenic sprouts (nm): wt = 198.8 ± 11.4 v hIGFREO = 136.6 ± 7.8, p=9.24634E-06). In contrast, after endothelium denuding arterial injury hIGFREO mice demonstrated accelerated endothelium regeneration (recovered area: wt = 40.27% ± 5.7 v hIGFREO = 57.25% ± 2.3, p=0.003). These data demonstrate a divergent role for the IGF-1R in angiogenesis and vascular repair and raise the possibility that manipulating IGF-1R in the endothelium is a novel approach to treat disorders of vascular growth and repair.
- © 2011 by American Heart Association, Inc.