Imrie, H orcid.org/0000-0002-1940-6604, Viswambharan, H orcid.org/0000-0002-7616-5026, Sukumar, P et al. (16 more authors) (2012) Novel Role of the IGF-1 Receptor in Endothelial Function and Repair: Studies in Endothelium-Targeted IGF-1 Receptor Transgenic Mice. Diabetes, 61 (9). pp. 2359-2368. ISSN 0012-1797
Abstract
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 [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. Insulin-resistant type 2 diabetes characterized by perturbation of the insulin/IGF-1 system is a multisystem disorder of nutrient homeostasis, cell growth, and tissue repair (1). As a result, type 2 diabetes is a major risk factor for the development of a range of disorders of human health, including occlusive coronary artery disease (2), peripheral vascular disease (3), stroke (4), chronic vascular ulcers (5), proliferative retinopathy (6), and nephropathy (7). A key hallmark of these pathologies is endothelial cell dysfunction characterized by a reduction in bioavailability of the signaling radical nitric oxide (NO). In the endothelium, insulin binding to its tyrosine kinase receptor stimulates release of NO (8). Insulin resistance at a whole-body level (9,10) and specific to the endothelium (11) leads to reduced bioavailability of NO, indicative of a critical role for insulin in regulating NO bioavailability. The insulin receptor (IR) and IGF-1 receptor (IGF-1R) are structurally similar—both composed of two extracellular α and two transmembrane β subunits linked by disulfide bonds (12). As a result, IGF-1R and IR can heterodimerize to form insulin-resistant hybrid receptors composed of one IGF-1R-αβ complex and one IR-αβ subunit complex (13,14). We recently demonstrated that reducing IGF-1R (by reducing the number of hybrid receptors) enhances insulin sensitivity and NO bioavailability in the endothelium (15). To examine the effect of increasing IGF-1R specifically in the endothelium on NO bioavailability, endothelial repair, and metabolic homeostasis, we generated a transgenic mouse with targeted overexpression of the human IGF-1R in the endothelium (hIGFREO).
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 07 Sep 2017 13:12 |
Last Modified: | 07 Sep 2017 13:12 |
Status: | Published |
Publisher: | American Diabetes Association |
Identification Number: | 10.2337/db11-1494 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:111262 |