Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats

G P Fadini, S Sartore, M Schiavon, M Albiero, I Baesso, A Cabrelle, C Agostini, A Avogaro
Diabetologia 2006, 49 (12): 3075-84

AIMS/HYPOTHESIS: A reduction in the number of endothelial progenitor cells (EPCs) is considered a plausible cause of increased cardiovascular risk in diabetes mellitus. The aim of this study was to test the hypothesis that weak bone marrow mobilisation is responsible for the decrease in circulating EPCs in diabetes.

MATERIALS AND METHODS: We employed a model of hindlimb ischaemia-reperfusion (I/R) injury to study mobilisation of EPCs in control and streptozotocin diabetic rats. EPCs were defined by flow cytometry as Sca-1(+) and Sca-1(+)c-kit(+) peripheral blood cells and further characterised by the expression of CD31, von Willebrand factor and fetal liver kinase-1. Capillary density was evaluated by immunofluorescent staining of vWF. We also determined plasma levels of stromal cell-derived factor (SDF-1) and vascular endothelial growth factor (VEGF) by ELISA and muscle expression of hypoxia-induced factor (HIF-1alpha) by Western blotting.

RESULTS: In control rats, EPCs showed a mobilisation curve within 7 days, while diabetic rats were completely unable to mobilise EPCs after I/R injury. As a consequence, diabetic rats showed no compensatory increase in muscle capillary density. Defective EPC mobilisation in diabetes was associated with altered release of SDF-1 and VEGF and inability to upregulate muscle HIF-1alpha. Both insulin administration and premedication with granulocyte-colony stimulating factor and stem cell factor led to partial recovery in post-ischaemic mobilisation of EPCs in diabetic rats.

CONCLUSIONS/INTERPRETATION: Defective ischaemia-induced bone marrow mobilisation of EPCs impedes compensatory angiogenesis in ischaemic tissues of diabetic animals. Growth factor administration together with blood glucose control may offer a rational therapeutic strategy for diabetic ischaemic syndromes.

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