Low levels of endothelial progenitor cells correlate with disease duration and activity in patients with Behçet's disease.

OBJECTIVES: We tested whether Behçet's disease (BD) is characterized by alterations of circulating endothelial progenitor cells (EPCs),which are involved in vascular homeostasis and repair. METHODS: We enrolled 30 BD patients and 27 matched healthy controls. EPCs were defined and measured by flow cytometry according to the expression of CD34, CD133 and KDR. RESULTS: We show that BD patients had significantly lower levels of CD34+KDR+ and CD34+CD133+KDR+ EPCs than controls. We found significant negative correlations between EPC phenotypes and BD duration, while there were positive correlations between CD34+KDR+ EPCs and both BD activity scores and C-reactive protein. The lower EPC levels with increasing disease duration was shown in univariate analysis and in multivariable analysis adjusted for possible confounders. CONCLUSION: This is the first report that BD is associated with progressive EPC decline. Reduction of EPCs may represent a mechanism of induction and/or progression of vascular injury in these patients.

Glucose tolerance is negatively associated with circulating progenitor cell levels.

AIMS/HYPOTHESIS: Circulating progenitor cells participate in cardiovascular homeostasis. Depletion of the pool of endothelial progenitor cells (EPCs) is associated with increased cardiovascular risk. Furthermore, EPCs are reduced in the presence of classical risk factors for atherosclerotic disease, including diabetes mellitus. This study was designed to evaluate progenitor cell levels in volunteers with different degrees of glucose tolerance. METHODS: Cardiovascular parameters and the levels of circulating CD34(+) and CD34(+) kinase insert domain receptor (KDR)(+) cells were determined in 219 middle-aged individuals with no pre-diagnosed alterations in carbohydrate metabolism. Glucose tolerance was determined by fasting and 2 h post-challenge glucose levels, with IFG and IGT considered as pre-diabetic states. RESULTS: CD34(+) and CD34(+)KDR(+) cells were significantly reduced in individuals who were found to have diabetes mellitus, and were negatively correlated with both fasting and post-challenge glucose in the whole population. While only CD34(+) cells, but not CD34(+)KDR(+) cells, were significantly reduced in pre-diabetic individuals, post-challenge glucose was an independent determinant of the levels of both CD34(+) and CD34(+)KDR(+) cells. CONCLUSIONS/INTERPRETATION: Glucose tolerance was negatively associated with progenitor cell levels in middle-aged healthy individuals. Depletion of endothelial progenitors with increasing fasting and post-meal glucose may be one cause of the high incidence of cardiovascular damage in individuals with pre-diabetes.

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

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.