Abstract 3695: Impairment of Endothelial Cell Repair in Mice Lacking the CXC Chemokine Receptor 3
Atherosclerosis is a systemic inflammatory disease. Within the atherosclerotic plaque, antigens are presented by macrophages/dendritic cells and trigger the activation of antigen-specific T-cells . Activated T-cells produce Th1 cytokines, which strongly induce the release of IP-10 and Mig from endothelial cells. These chemokines counteract with its receptor CXCR3 and direct the migration of inflammatory cells from the bone marrow toward sites of inflammation. We postulate that bone marrow-derived endothelial progenitor cells (EPC) express the CXCR3 receptor and are attracted to the lesion site by interaction with IFN-gamma inducible chemokines. CD133+/CD34− and CD34+ /VEGFR2+ EPC express the CXCR3 receptor as determined in PCR analysis and flow cytometry. The migratory capacity of EPC towards IP-10 was reduced with increasing concentrations whereas MIG was able to dose-dependently stimulate migration. No differences between both chemokines were observed concerning adhesion capacity (flow-mediated adhesion assays). IP-10 and MIG enhanced dose-dependently the adhesion of EPC on TNF-alpha stimulated endothelial cells. Blocking experiments using antibody directed against the CXCR3 receptor prevented EPC adhesion. In order to study the in vivo relevance of CXCR3 in re-endothelialization, we performed endothelial cell denudation experiments in CXCR3−/− mice and controls. The re-endothelialization process was significantly delayed in CXCR3−/− mice compared to controls. Surprisingly, the number of circulating Sca1/c-kit positive EPC was significantly higher in CXCR3-deficient mice compared to controls whereas on the bone marrow level, the number of sca1/c-kit positive EPC was decreased in CXCR3−/− mice compared to controls. The Th1 associated inflammatory response after vascular damage not only attracts inflammatory cells but also CXCR3+ EPC which appear to contribute to the restoration of the endothelium after endothelial cell damage. These results are in line with a recently published observation that EPC recruitment in asthma is Th1 and Th2 dependent and results in increased microvessel density. Our results indicate a pivotal role of the CXCR3 receptor in EPC mobilization and homing.