Article Text

PDF

C Insulin resistance impairs angiogenic progenitor cell function and delays endothelial repair following vascular injury
  1. M B Kahn,
  2. N Yuldasheva,
  3. R Cubbon,
  4. J Surr,
  5. S Rashid,
  6. H Viswambharan,
  7. H Imrie,
  8. A Abbas,
  9. A Rajwani,
  10. M Gage,
  11. M T Kearney,
  12. S Wheatcroft
  1. Leeds University, Leeds, UK

Abstract

Introduction Insulin-resistance, the primary metabolic abnormality underpinning type-2-diabetes mellitus (T2DM) and obesity, is an important risk factor for the development of atherosclerotic cardiovascular disease. Circulating-angiogenic-progenitor-cells (APCs) participate in endothelial-repair following 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 per se adversely affects APCs and endothelial-regeneration.

Research Design and Methods We quantified APCs and assessed APC-mobilisation and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial-regeneration following femoral artery wire-injury was also quantified at time intervals after denudation and following APC transfusion.

Results The metabolic phenotype of IRKO mice was consistent with compensated insulin resistance, with hyperinsulinaemia after a glucose challenge but a normal blood glucose response to a glucose tolerance test. IRKO mice had fewer circulating Sca-1+/Flk-1+ APCs than WT mice at baseline. Culture of mononuclear-cells demonstrated that IRKO mice had fewer APCs in peripheral-blood, but not in bone-marrow or spleen, suggestive of a mobilisation defect. Defective VEGF-stimulated APC mobilisation was confirmed in IRKO mice, consistent with reduced eNOS expression in bone marrow and impaired vascular eNOS activity. Paracrine-angiogenic-activity of APCs from IRKO mice was impaired compared to those from WT animals. Endothelial-regeneration of the femoral artery following denuding wire-injury was delayed in IRKO mice compared to WT (re-endothelialised area 35.8±4.8% vs 66.6±5.2% at day 5 following injury and 35.6±4.8% vs 59.8±6.6% at day 7; P<0.05) (Abstract C Figure 1A). Transfusion of mononuclear-cells from WT mice normalised the impaired endothelial-regeneration in IRKO mice (57±4% vs 25±5%; p<0.002). Transfusion of c-kit+ bone-marrow cells from WT mice also restored endothelial-regeneration in IRKO mice (62±2% vs 25±5%; p<0.002). However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial-repair (62±2% vs 45±4%; p<0.02) (Abstract C Figure 1B).

Abstract C Figure 1

(A) Time-dependent endothelial regeneration following vascular injury (n=5 mice per group; *denotes p<0.05). (B) Effects on endothelial regeneration 5 days after wire-injury of transfusion of spleen-derived MNCs or BM-derived c-kit (CD117)+ve cells from WT or IRKO mice (n=4 mice per group).

Conclusions Insulin-resistance impairs APC function and delays endothelial-regeneration following arterial injury. These findings support the hypothesis that insulin-resistance per se is sufficient to jeopardise endogenous vascular repair. Defective endothelial-repair may be normalised by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals. These data may have important implications for the development of therapeutic strategies for insulin-resistance associated cardiovascular disease.

  • Insulin resistance
  • angiogenic progenitor cells
  • endothelial repair

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.