Novel role of the IGF-1 receptor in endothelial function and repair: Studies in endothelium-targeted IGF-1 receptor transgenic mice

摘要

We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice hIGFREO) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to N G- monomethyl-L-arginine mean (SEM) wild type 106 (30); hIGFREO 48 (10); P 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean SEM wild type 170 25, hIGFREO 58 3; P = 0.04) and insulin-stimulated NO release (mean SEM wild type 4,500 AU 1,000, hIGFREO 1,500 AU 700; P 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean SEM percent recovered area, wild type 57 2, hIGFREO 47 5; P 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair.