Abstract 5041: Insulin Resistance Reduces Circulating Endothelial Progenitor Cells and Impairs Endothelial Regeneration Following Wire-induced Vascular Injury
Introduction: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration following damage accrued through exposure to various risk factors. Type 2 diabetes is associated with reduced EPC numbers, EPC dysfunction and delayed endothelial repair. However, it remains unknown whether insulin resistance per se has an effect on EPCs or endothelial regeneration.
Methods: We assessed metabolic and endothelial function, circulating, spleen- and bone marrow-derived EPCs and endothelial regeneration following wire-injury in mice hemizygous for deletion of the insulin receptor (IR+/−) and their littermate wild type (WT) controls. Results: The metabolic phenotype of IR+/− mice was consistent with compensated insulin resistance, with hyperinsulinaemia after a glucose challenge but a normal blood glucose response to a glucose tolerance test. Endothelial function was impaired in aorta from IR+/− mice, with decreased basal nitric oxide production and blunted eNOS activity in response to insulin. Sca-1/VEGFR-2 positive EPCs, measured in peripheral blood by flow cytometry, were reduced in IR+/− mice compared to WT controls (67±6 vs 87±6 cells/100 000 events; P<0.05). Culture of mononuclear cells from peripheral blood, spleen and bone marrow revealed significantly reduced numbers of circulating EPCs in IR+/− mice compared to WT controls (P<0.05), however there was no difference in the number of spleen- and bone marrow-derived EPCs. Endothelial regeneration, assessed by Evan’s blue staining of femoral artery at intervals following denuding wire-injury, was significantly delayed in IR+/− mice compared to WT controls (reendothelialised 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 following injury; P<0.05).
Conclusions: These novel data demonstrate that mild insulin resistance reduces the number of basal circulating EPCs and delays endothelial regeneration following injury. The findings support the hypothesis that insulin resistance may promote atherosclerosis by adversely affecting the balance between endothelial damage and repair.