Importance of CXC Chemokine Receptor 2 in the Homing of Human Peripheral Blood Endothelial Progenitor Cells to Sites of Arterial Injury

Abstract

Circulating endothelial progenitor cells (EPCs) may contribute to endothelial regeneration; however, the exact mechanisms of their arterial homing remain elusive. We examined the role of the angiogenic chemokine receptor CXCR2 in the homing of human EPCs. Isolated EPCs expressed CXCR2 together with kinase insert domain-containing receptor, CD31, vascular endothelial cadherin, and CXCR4. Adhesion assays under flow conditions showed that EPCs preferentially adhered to beta(2)-integrin ligands, that firm arrest on fibronectin or fibrinogen was enhanced by the CXCR2 ligands CXCL1 or CXCL7, and that blockade of CXCR2 significantly reduced EPC adhesion on platelet-coated endothelial matrix. This was corroborated by the involvement of CXCR2 in EPC recruitment to denuded areas of murine carotid arteries ex vivo and in vivo. Notably, blocking CXCR2 inhibited the incorporation of human EPCs expressing CXCR2 at sites of arterial injury in athymic nude mice. Immunoreactivity for the beta-thromboglobulin isoform CXCL7 was observed in murine platelets and denuded smooth muscle cells (SMCs) early after wire injury, and transcripts for CXCL7 and CXCL1 were detected in isolated human arterial SMCs. Human KDR(+)CXCR2(+) cells showed better in situ adhesion to injured murine carotid arteries than KDR(+)CXCR2(-) cells, were predominantly CD14(+), and improved CXCR2-dependent endothelial recovery after injury in nude mice. In conclusion, our data clearly demonstrate the importance of CXCR2 for the homing of circulating EPCs to sites of arterial injury and for endothelial recovery in vivo.