Endothelial-monocyte-activating polypeptide II induces migration of endothelial progenitor cells via the chemokine receptor CXCR3.
OBJECTIVE
Recruitment of endothelial progenitor cells to the sites of ischemia has recently been suggested as a mechanism of tissue repair. Here we address the hypothesis that the hypoxia-inducible full-length endothelial-monocyte-activating polypeptide II (EMAP II) provides a mechanism to recruit late outgrowth highly proliferating endothelial progenitor cells (EPCs).


METHODS
We tested in a transwell migration assay EMAP II for its ability to induce migration of EPCs. Furthermore, we measured changes in cellular calcium levels in EPC to assess the ability of EMAP II to induce intracellular signaling. Finally, we employed neutralizing antibodies and binding competition studies in order to identify the receptor mediating these activities of EMAP II in EPCs.


RESULTS
EMAP II elicits dose-dependent migration and intracellular calcium mobilization in EPCs. Functional blocking and binding studies with radiolabeled interferon-gamma-induced protein (IP-10) indicate that EMAP II employs the CXCR3 receptor for these activities in EPCs. Indeed, EMAP II-induced migration of EPCs can be abolished by prior treatment of cells with anti-CXCR3 antibodies or with IP-10.


CONCLUSIONS
These data suggests a novel function for EMAP II and a hitherto undescribed role of the CXCR3 chemokine receptor in EPC recruitment.
Hou
Yonghao
Y
Department of Cellular and Integrative Physiology and Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Plett
P Artur
PA
Ingram
David A
DA
Rajashekhar
Gangaraju
G
Orschell
Christie M
CM
Yoder
Mervin C
MC
March
Keith L
KL
Clauss
Matthias
M
D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*
C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; C077219:small inducible cytokine subfamily E, member 1