Objective-Increased risk of cardiovascular disease in patients with chronic renal failure (CRF) has been explained by accelerated atherosclerosis and impaired angiogenesis, in which endothelial progenitor cells (EPCs) may play key roles. We hypothesized that altered EPC biology may contribute to the pathophysiology of CRF. Methods and Results-EPCs were isolated from CRF patients on maintenance hemodialysis (nϭ44) and from a normal control group (nϭ30). CRF patients showed markedly decreased numbers of EPC (44.6%) and colonies (75.3%) when compared with the controls (PϽ0.001). These findings were corroborated by 30.5% decrease in EPC migratory function in response to vascular endothelial growth factor (VEGF) (Pϭ0. T he lifespan of patients with chronic renal failure (CRF) is reduced, and coronary artery disease is the most important cause of morbidity and mortality in these patients. 1,2 Even the results of therapeutic strategies such as percutaneous coronary intervention and bypass surgery have shown poor procedural success rates and dismal long-term eventfree survival in CRF patients. 3,4 Most of the increased cardiovascular morbidity and mortality in CRF has been accounted for by the rapid progression of atherosclerosis, which is clinically shown to be accelerated in CRF. 5,6 Experimental studies have also shown that even mild renal dysfunction causes a dramatic acceleration of atherosclerosis. 7 Angiogenesis, which is an essential compensation for myocardial ischemia, is also impaired in CRF. 8 However the mechanism underlying the acceleration of atherosclerosis and impaired angiogenesis by CRF has not been examined closely. Although the phenomenon has been partially explained by the higher prevalence of established risk factors in CRF, such as hypertension, abnormal carbohydrate metabolism, and increased low density lipoprotein (LDL) cholesterol, the extent and severity of cardiovascular disease is clearly disproportionately high relative to the underlying risk factor profile. 9,10 Recent studies have identified that normal adults have a small amount of circulating endothelial progenitor cell (EPC) in the peripheral blood. In response to cytokine stimulation and ischemic insult, these cells are mobilized from bone marrow, home to the ischemic tissue, and contribute to neovascularization and angiogenesis. 11-14 Moreover, EPC is regarded to have a key role in the maintenance of vascular integrity and to act as "repair" cells in response to the endothelial injury, 15,16 which has been regarded as an initial step in atherosclerosis and a result of the actions of various cardiovascular risk factors. 17 Current data suggest that decrease in circulating EPC contributes not only to impaired angiogenesis but also to the progression of atherosclerosis, 18 and patients at risk for coronary artery disease have a decreased number of circulating EPC with impaired activity. 19 -22 Therefore, we reasoned that EPC, which is critical for neovascularization and the maintenance of vascular integrity, Methods Study SubjectsWe...

Endothelial progenitor cells (EPCs) act as endothelial precursors that promote new blood vessel formation and increase angiogenesis by secreting growth factors and cytokines in ischemic tissues. These facts prompt the hypothesis that EPC transplantation should accelerate the wound-repair process by facilitating neovascularization and the production of various molecules related to wound healing. In a murine dermal excisional wound model, EPC transplantation accelerated wound re-epithelialization compared with the transplantation of mature endothelial cells (ECs) in control mice. When the wounds were analyzed immunohistochemically, the EPCtransplanted group exhibited significantly more monocytes/ macrophages in the wound at day 5 after injury than did the EC-transplanted group. This observation is consistent with enzyme-linked immunosorbent assay results showing that EPCs produced in abundance several chemoattractants of monocytes and macrophages that are known to play a pivotal role in the early phase of wound healing. At day 14 after injury, the EPC-transplanted group showed a statistically significant increase in vascular density in the granulation tissue relative to that of the EC-transplanted group. Fluorescence microscopy revealed that EPCs preferentially moved into the wound and were directly incorporated into newly formed capillaries in the granulation tissue. These results suggest that EPC transplantation will be useful in dermal wound repair and skin regeneration, because EPCs both promote the recruitment of monocytes/macrophages into the wound and increase neovascularization. Stem Cells 2005;23:1571-1578

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