Novel Role of the IGF-1 Receptor in Endothelial Function and Repair
Studies in Endothelium-Targeted IGF-1 Receptor Transgenic Mice
- Helen Imrie1,
- Hema Viswambharan1,
- Piruthivi Sukumar1,
- Afroze Abbas1,
- Richard M. Cubbon1,
- Nadira Yuldasheva1,
- Matthew Gage1,
- Jessica Smith1,
- Stacey Galloway1,
- Anna Skromna1,
- Sheik Taqweer Rashid1,
- T. Simon Futers1,
- Shouhong Xuan2,
- V. Kate Gatenby1,
- Peter J. Grant1,
- Keith M. Channon3,
- David J. Beech1,
- Stephen B. Wheatcroft1 and
- Mark T. Kearney1⇓
- 1Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, U.K.
- 2Department of Genetics and Development, Columbia University, New York, New York
- 3University of Oxford British Heart Foundation Centre of Research Excellence, Oxford, U.K.
- Corresponding author: Mark T. Kearney, .
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 NG-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 ; 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1494/-/DC1.
See accompanying commentary, p. 2225.
- Received October 25, 2011.
- Accepted April 18, 2012.
- © 2012 by the American Diabetes Association.
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