Insulin resistance, the primary metabolic abnormality underpinning type 2 diabetes mellitus and obesity, is an important risk factor for the development of cardiovascular disease. Endothelial dysfunction represents one of the earliest phases in the natural . history of atherosclerosis and is normally offset in health by various endogenous repair processes. Circulating endothelial progenitor cells (EPCs) participate in endothelial repair following arterial injury. Type 2 diabetes is associated with fewer circulating EPCs, EPC dysfunction and impaired endothelial-repair. I set out to determine whether insulin-resistance per se adversely affects EPC mediated endothelial-regeneration using mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. The metabolic phenotype of IRKO mice was consistent with compensated insulin resistance. Flow cytometry demonstrated that IRKO mice had fewer circulating EPCs than WT mice. Culture of mononuclear-cells confirmed that IRKO mice had fewer EPCs in peripheral-blood, but not in bone-marrow or spleen, suggesting a mobilization defect. Defective VEGF-stimulated EPC mobilization was confirmed in IRKO mice, consistent with reduced eNOS expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of EPCs 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. Transfusion of mononuclear-cells and c-kit bone-marrow cells from WT mice normalized the impaired endothelial-regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial-repair. My data suggest that insulin-resistance impairs EPC 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 EPCs 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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:550287 |
| Date | January 2011 |
| Creators | Kahn, Matthew Benjamin |
| Publisher | University of Leeds |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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