Insulin Resistance Impairs Circulating Angiogenic Progenitor Cell Function and Delays Endothelial Regeneration

Abstract

OBJECTIVECirculating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration.RESEARCH DESIGN AND METHODSWe quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion.RESULTSIRKO mice, although glucose tolerant, had fewer circulating Sca-1+/Flk-1+ APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor–stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit+ bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial repair.CONCLUSIONSInsulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals.

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

“…This observation contrasts with our recent findings in mice with haploinsufficiency of the insulin receptor in which endothelial regeneration was compromised 4 and implies divergent functional consequences of downregulation of the 2 tyrosine kinase receptors on vascular repair. We did not uncover any differences in angiogenic sprouting between vessels from IGF1R +/− and WT mice in vitro, suggesting that alterations in circulating progenitor cells rather than native endothelial cells likely contributed to the enhanced endothelial regeneration observed in vivo.…”

“…4 Splenectomized WT mice were infused with WT or IGF1R +/− bone marrow-derived CD117 + (c-kit + ) cells or saline after femoral artery injury. Re-endothelialization was significantly enhanced by infusion of IGF1R +/− CD117 + bone marrow-derived cells when compared with infusion of WT cells or cell-free saline ( Figure 5A and 5B).…”

“…2 Recent studies support a prominent role for impairment of nitric oxide (NO)-dependent endothelial cell repair/replacement in diabetes mellitus-related vascular disease. 3,4 Indeed, insulin resistance, the primary metabolic disturbance underpinning type 2 diabetes mellitus, is associated with delayed endothelial repair in the absence of overt glycemia. 4 We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R), which acts as the principal tyrosine kinase receptor delivering cues for cellular and whole organism growth, is a negative regulator of NO bioavailability and insulin sensitivity in the endothelium.…”

“…3,4 Indeed, insulin resistance, the primary metabolic disturbance underpinning type 2 diabetes mellitus, is associated with delayed endothelial repair in the absence of overt glycemia. 4 We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R), which acts as the principal tyrosine kinase receptor delivering cues for cellular and whole organism growth, is a negative regulator of NO bioavailability and insulin sensitivity in the endothelium. 5 In mice with haploinsufficiency of the IGF1R, we observed a phenotype of enhanced whole-body insulin sensitivity, enhanced insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS), and increased basal NO generation.…”

Vasculogenesis in Diabetes-Associated Diseases: Unraveling the Diabetic Paradox

“…Additionally, it was also reported that after arterial injury in hemizygous knockout mice for the insulin receptor (IRKO), EPCs activities were altered and endothelial regeneration delayed. This defective endothelial repair could be normalized by transfusion of progenitor cells from insulin-sensitive animals, but not from insulin-resistant animals (Kahn et al, 2011). However, it is thought that EPCs biological modifications are mostly affected by IR in an indirect fashion, through the increase in ROS and also by the activation of pro-inflammatory cytokines (Cubbon et al, 2007;2009;Houstis et al, 2006).…”