Novel Role of the IGF-1 Receptor in Endothelial Function and Repair

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.

Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

“…Signal cascades induced by IGF-1 mediate many cellular responses, including proliferation, differentiation, and angiogenesis (8, 33), and are also involved in tumor angiogenesis and developmental neovascularization in human and zebrafish (12,13,34). A recent study demonstrated that IGF-1R activation by IGF-1 promotes differentiation of stem cells into mesoderm and endothelial progenitor cells into mature ECs, indicating IGF-1 as a potential drug for enabling vascular regeneration (12).…”

“…A recent study demonstrated that IGF-1R activation by IGF-1 promotes differentiation of stem cells into mesoderm and endothelial progenitor cells into mature ECs, indicating IGF-1 as a potential drug for enabling vascular regeneration (12). Moreover, endothelium-targeted IGF-1R transgenic mice enhance endothelial remodeling and vasorelaxation (13), suggesting that an activator of IGF-1R may be a useful therapeutic strategy to treat vascular repair and hypertension disorders. In this study, we found that Rg5 activated common angiogenic signal pathways via IGF-1R.…”

“…Moreover, IGF-1R has also been shown to mediate neovascularization in human lung development and zebrafish cardiovascular development (10,11) and promote vasculogenesis via differentiation of embryonic stem cells into endothelial cells (12). Moreover, a recent study determined that mouse overexpression of human IGF-1R in the endothelium enhances endothelium regeneration after denuding arterial injury and vasorelaxation (13), suggesting that IGF-1R activation is a useful target for treating vascular repair and hypertension disorders. Thus, IGF-1R agonists can be used as a beneficial means to treat human diseases with vascular dysfunction.…”

Endothelial cells and the IGF system

“…Furthermore, infusion of these cells into WT mice increased endothelial repair without altering atherosclerotic lesion formation. Overexpression of IGF1 receptors on endothelial cells increased hybrid formation and reduced NO bioavailability (Imrie et al 2012). However, perhaps surprisingly, endothelial regeneration was enhanced by IGF1 receptor overexpression after arterial denudation.…”

Examining the Role of Insulin in the Regulation of Cardiovascular Health

“…Insulin-stimulated NO synthesis in cultured endothelial cells is independent of Ca 2+ concentration but dependent on IRS1-PI3K-PDK1-Akt pathway activation [1,3,7]. IGF-1 has been reported to be a markedly less effective stimulus for NO synthesis -indeed, recent elegant studies using mice with an endothelial-specific knockdown of IGFR or overexpression of IGFR have reported that the IGFR is a negative regulator of insulin-stimulated NO synthesis, perhaps due to formation of IR-IGFR heterodimers that are less sensitive to insulin than IR homodimers [22,23]. eNOS is subject to reversible phosphorylation at several sites [24], and Akt-mediated phosphorylation of eNOS at Ser1177, which reduces the requirement for Ca 2+ and permits NO synthesis in the absence of increased cellular Ca 2+ is required for insulin-stimulated NO synthesis in cultured endothelial cells ( Figure 2) [7,24].…”