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Objective: Circulating endothelial progenitor cells (EPCs), responsible for neoangiogenesis and vascular repair, negatively correlate with vascular dysfunction and atherosclerotic risk factors. Because obesity may have a crucial role in the development of endothelial dysfunction, this study evaluated the number and proliferative activity of circulating human EPCs in obese (body mass index (BMI) ¼ 48±9, n ¼ 45) compared with lean (23±2, n ¼ 45) volunteers. Methods: EPCs were quantified after isolation of peripheral blood mononuclear cells (PBMCs) using fluorescence-activated cell sorting analyses. In addition, plated PBMCs developed colony-forming units (CFUs) from which 'outgrowth' endothelial cells (OECs) sprouted and differentiated into mature endothelial cells. Growth rates were monitored by periodical microscopic evaluation. Cell-cycle protein expression was determined by western blot analyses. Results: BMI negatively correlated (Po0.01) with the number of.500) and CD133 þ /KDR þ (r ¼ À0.282) EPCs. Insulin, leptin, HbA 1c , high-sensitivity C-reactive protein and hypertension, as well as diminished high-density lipoprotein and apolipoprotein A1, were not only associated with obesity but also with significantly reduced EPC levels. Applying selective culture conditions, EPC-CFUs differentiated into OECs that proliferated more slowly when derived from obese compared with lean subjects (obese: 19.9 ± 2.2% vs lean: 30.9 ± 3.2% grown area per week, Po0.01). The reduced proliferation was reflected by decreased (Po0.05, n ¼ 24 for each group) expression of cell-cyclepromoting cyclins and E2F-1, by hypophosphorylation of retinoblastoma protein and by increased (Po0.05, n ¼ 24 for each group) expression of the cell-cycle inhibitor p21 WAFÀ1/Cip1 . Conclusions: Reduced numbers of EPCs along with their premature senescence, as shown in this study, could function as early contributors to the development and progression of vascular dysfunction in obesity.

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