Enhancing vascular endothelial repair in the setting of insulin resistance: effects of insulin-like growth factor binding protein-1

Insulin resistance (IR) leads to the development of type 2 diabetes mellitus and predisposes to cardiovascular disease (CVD) through its link with endothelial dysfunction. Cardiovascular risk factors and iatrogenic damage lead to biochemical and structural injury to the endothelium. Endogenous repair mechanisms are in place to regenerate injured endothelium. Insulin resistance has recently been shown to impair endothelial repair. The endogenously produced circulating insulin-like growth factor binding protein-1 (IGFBP-1) is potentially protective in the vasculature by stimulating nitric oxide production and enhancing insulin signalling in the endothelium. Cross-sectional studies have shown an association between low IGFBP-1 levels and CVD. This raises the possibility of exploiting IGFBP-1 therapeutically to prevent CVD in patients with diabetes. This project investigated whether IGFBP-1 enhances vascular endothelial repair in insulin resistant mice in vivo and probed potential molecular mechanisms by examining the effects of IGFBP-1 on human endothelial cells (EC) and angiogenic progenitor cells (APCs) in vitro. Endothelial regeneration was enhanced following arterial endothelium-denuding injury in IRKO mice by over-expressing human IGFBP-1. This was not explained by altered abundance or function of APCs. Incubation with IGFBP-1 significantly enhanced the ability of human EC to adhere to and regenerate denuded human vein ex vivo. In EC, IR was mimicked by the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) which significantly inhibited EC migration and proliferation in vitro. Co-incubation with IGFBP-1 restored the migratory and proliferative capacity of EC. IGFBP-1 significantly increased FAK phosphorylation, induced rapid activation of RhoA, and increased expression of α5β1 and αVβ3 integrins in EC. These multifactorial effects of IGFBP-1 on EC responses and acceleration of endothelial regeneration in mice raise the possibility that manipulating IGFBP-1 could be a strategy to enhance endothelial repair in humans with IR.