Abstract 15090: Upregulation of Cxcr4 Gene Expression Enhances in vivo Reendothelialization of Human Endothelial Progenitor Cells
Background: Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair after artery injury. The chemokine receptor CXCR4 is a key modulator of EPCs homing to impaired artery and reendothelialization. In this study, we addressed the hypothesis that upregulation of CXCR4 gene expression could enhance in vivo reendothelialization capacity of EPCs.
Methods: In vitro, human EPCs from healthy volunteer peripheral blood were transfected with the adenovirus serotype 5 encoding the human CXCR4 gene. CXCR4 gene transfer augmented in vitro stromal-derived factor-1-induced migratory function of EPCs and enhanced tumor necrosis factor-α-activated adhesive response of EPCs to human umbilical vein endothelial cell monolayers. To determine if CXCR4 gene transfer may facilitate therapeutic reendothelialization, the effect of EPCs on in vivo reendothelialization was examined in a nude mice carotid artery injury model.
Results: Transplantation of EPCs transduced with CXCR4 significantly accelerated in vivo reendothelialization compared with EPCs transduced with enhanced green fluorescent protein and nontransduced EPCs. Furthermore, the phosphorylation of Janus kinase-2(JAK-2), a CXCR4 downstream signaling, was also increased in EPCs with CXCR4 gene transfer. Both the enhanced in vitro function and in vivo reendothelialization capacity of EPCs transduced with CXCR4 were abolished by neutralizing antibodies against CXCR4 or JAK-2 inhibitor AG490.
Conclusions: The present study is the first time to demonstrate that increased CXCR4 gene expression by gene transfer contributes to enhanced in vivo reendothelialization capacity of EPCs. Up-regulation of CXCR4 in human EPCs may become a novel therapeutic target for endothelial repair.
- © 2010 by American Heart Association, Inc.