Haploinsufficiency of the Insulin-Like Growth Factor-1 Receptor Enhances Endothelial Repair and Favorably Modifies Angiogenic Progenitor Cell Phenotype

Abstract

Objectives— Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair. Approach and Results— We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R +/− ). Endothelial regeneration after arterial injury was accelerated in IGF1R +/− mice. Although the yield of angiogenic progenitor cells was lower in IGF1R +/− mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R +/− bone marrow–derived CD117 + cells into wild-type mice. IGF1R +/− cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation. Conclusions— Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow–derived CD117 + cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury.

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

“…21 In order to examine this possibility, we isolated circulating CD11b + myeloid cells from hIRECO and wild type littermates, as previously described. 22 There was no difference in total circulating CD11b + or monocyte count (Supplemental Figure hIRECO mice have normal glucose tolerance and blood pressure and elevated plasma nitrite. Over-expression of the IR in the endothelium had no effect on fasting glucose, ( Figure 3A) fasting insulin levels ( Figure 3B) or blood pressure levels at the age of 3 months ( Figure 3C).…”

Endothelial cells and the IGF system

“…Haploinsufficient Igf1r C/K mice had decreased IGF1 receptors, enhanced insulin-mediated glucose disposal, restored insulin-mediated aortic vasorelaxation, and increased insulin-stimulated endothelial cell NO release (Abbas et al 2011). Haploinsufficient Igf1r C/K mice also had fewer angiogenic progenitor cells than WT mice, but these cells had increased adhesion to fibronectin, increased IGF1 secretion and enhanced tube formation (Yuldasheva et al 2014). Furthermore, infusion of these cells into WT mice increased endothelial repair without altering atherosclerotic lesion formation.…”

Endothelium

“…Manipulating insulin-like growth factor-1 receptor expression in bone marrow cells seems also of interest to improve endothelial repair after arterial wall injury. 26 Insulin-like growth factor-1 receptor haploinsufficiency in bone marrow cells accelerates endothelial regeneration in a murine model of vascular wire injury and does not alter the formation of atherosclerotic lesions. Despite their lower number, angiogenic progenitors display enhanced adhesion, increased release of insulin-like growth factor-1 and enhanced angiogenic capacity.…”