Novel role of the IGF-1 receptor in endothelial function and repair: studies in endothelium-targeted IGF-1 receptor transgenic mice
| العنوان: | Novel role of the IGF-1 receptor in endothelial function and repair: studies in endothelium-targeted IGF-1 receptor transgenic mice |
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| المؤلفون: | Imrie, H, Viswambharan, H, Sukumar, P, Abbas, A, Cubbon, RM, Yuldasheva, N, Gage, M, Smith, J, Galloway, S, Skromna, A, Rashid, ST, Futers, TS, Xuan, S, Gatenby, VK, Grant, PJ, Channon, KM, Beech, DJ, Wheatcroft, SB, Kearney, MT |
| المصدر: | Diabetes. 61(9) |
| سنة النشر: | 2012 |
| الوصف: | 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). |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1939-327X 0012-1797 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::28e8d93af410d48a6b206ec118d37f82 http://ora.ox.ac.uk/objects/uuid:396eae77-dd2b-4b0a-b59d-95d6b2095146 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.dedup.wf.001..28e8d93af410d48a6b206ec118d37f82 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
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