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Vascular restenosis remains a major obstacle to long-term success after vascular intervention. Circulating progenitor cells have been implicated in restenosis, and yet it has remained unclear if these cells, particularly nonendothelial progenitors, have an active role in this pathologic process. We hypothesized that circulating CD34+/c-kit+ progenitors would increase after vascular injury, mirrored by changes in the injury signal, stromal cell-derived factor 1α (sdf1α). We further postulated that an antibody-based depletion would mitigate progenitor surge and, in turn, reduce restenosis in a murine model.C57BL6 mice underwent wire injury of the femoral artery and were compared with mice with sham surgery and vessel ligation by flow cytometry as well as by sdf1α enzyme-linked immunosorbent assay of peripheral blood. Next, injured C57BL6 mice treated with a depleting antibody toward the progenitor marker sca-1 or with an isotype control were compared in terms of sdf1α as well as enumeration of progenitors. At 28 days, restenosis was quantified between sca-1- and isotype-treated animals.Wire injury generated an increase in sdf1α as well as a surge of CD34+/c-kit+ progenitors relative to nonsurgical controls (P= .005). Treatment with sca-1 antibody ablated the peripheral surge compared with isotype-treated, injured animals (P= .02), and sca progenitor depletion reduced the 28-day intima to media ratio in a statistically significant fashion compared with either nontreated (P= .04) or isotype-treated (P= .036) animals.Our study has demonstrated that sca-1 antibody reduces both progenitor surge and vascular restenosis after endoluminal vascular injury in a murine model. This suggests that circulating progenitors play an active role in restenotic disease.Vascular restenosis is a clinically important complication leading to failure of up to half of open and endovascular interventions in under 5 years. As a result, this pathologic process affects long-term patient outcomes and increases health care costs. Progenitor cells circulating in the blood have been suggested to contribute to restenosis, but it has not been demonstrated if these cells play an active role in this pathologic process. The results of this study suggest that circulating progenitor cells may represent an important contributor to restenosis and that blockade of these cells may represent an approach to prevent this life- and limb-threatening complication.