SDF-1α involved in mobilization and recruitment of endothelial progenitor cells after arterial injury in mice

Abstract

Endothelial progenitor cells (EPCs) can be mobilized by cytokines and recruited to sites of neovascularization and neointima, where they differentiate into mature endothelial cells. It is thought that stromal cell-derived factor-1alpha (SDF-1alpha) is involved in ischemia-mediated mobilization and homing of EPCs and in vascular injury-mediated mobilization and homing of vascular smooth muscle progenitor cells. It is unclear if SDF-1alpha plays a similar role in the mobilization and recruitment of EPCs after vascular injury. SDF-1alpha was detected by reverse transcriptase-polymerase chain reaction and Western blot in the carotid arteries of mice at different times after wire-induced injury. SDF-1alpha expression was evident at 1 day and peaked at 3 days after arterial injury. In an ELISA test, a rise in the plasmatic concentration of SDF-1alpha and a significant reduction of SDF-1alpha bone marrow (BM) concentration were noticed at different times after injury (Days 1, 3, and 7). Fluorescence-activated cell sorting analysis revealed that the amount of circulating EPCs was increased shortly after induction of vascular injury and persisted for up to 7 days. In SDF-1alpha antibody-treated mice, only a small rise in the amount of circulating EPCs was noted at 1 day. En-face microscopy and immunohistochemical analysis showed that systemic injection of EPCs after vascular injury demonstrated their recruitment to the sites of endothelial denudation, where they could adopt an endothelium-like phenotype and accelerate reendothelialization of the injured arteries. Fewer CXCR4 (receptor of SDF-1)-blocked EPCs could home to the sites of endothelial denudation, and accelerated reendothelialization was not observed in this group. Treatment of mice after carotid injury with a neutralizing SDF-1alpha monoclonal antibody for 2 weeks reduced reendothelialization area. We demonstrated for the first time that SDF-1alpha plays an important role in reendothelialization after vascular injury in mice. This contribution appears to be attributable to SDF-1alpha-dependent mobilization and recruitment of circulating EPCs.