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

Abstract

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-1α) 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-1α. Both insulin administration and premedication with granulocyte-colony stimulating factor and stem cell factor led to partial recovery in postischaemic 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.

Trafficking of Multipotent Mesenchymal Stromal Cells from Maternal Circulation Through the Placenta Involves Vascular Endothelial Growth Factor Receptor-1 and Integrins

“…VEGF-A concentration in human umbilical vein plasma was low but was significantly greater than that in maternal plasma (10.7 Ϯ 4.3 pg/ml vs. 1.3 Ϯ 0.2 pg/ml; p Ͻ .001). The VEGF-A concentration in maternal rat venous blood plasma was consistent with a prior report [40] and was similar in the samples from maternal rat artery. However, VEGF-A was significantly higher in fetal rat plasma The hMSCs spontaneously adhered to fibronectin and laminin, and adhesion was significantly increased as VEGF-A concentration increased (supplemental online Fig.…”

Circulating endothelial progenitor cells, endothelial function, carotid intima–media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria

“…In an animal model of hindlimb ischaemia-reperfusion injury, insulin treatment was found to improve the mobilisation of EPCs from bone marrow [45].…”

Significance of Endothelial Progenitor Cells in Subjects With Diabetes

“…We have recently confirmed this hypothesis, showing that bone marrow mobilization of EPCs after ischemia-reperfusion injury is defective in diabetic rats. Inability to mobilize EPCs was associated with downregulation of HIF-1␣ and weakened release of marrowstimulating factors, such as VEGF and SDF-1, ultimately leading to insufficient compensatory angiogenesis (19). Another study has shown that progenitor cell mobilization restored blood flow in diabetic mice (20).…”

“…Furthermore, activation of mitogen-activated protein kinases has been revealed as a potential mechanism of EPC dysfunction induced by high glucose (30). A definite demonstration is that correction of hyperglycemia by insulin therapy (19,22) can indeed restore the normal EPC pool.…”