The Journal of Experimental Medicine
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Published online 9 January 2006 doi:10.1084/jem.20050459
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 153-163
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ARTICLE

 Functional disruption of {alpha}4 integrin mobilizes bone marrow–derived endothelial progenitors and augments ischemic neovascularization

Gangjian Qin1, Masaaki Ii1, Marcy Silver1, Andrea Wecker1, Evelyn Bord1, Hong Ma1, Mary Gavin1, David A. Goukassian1, Young-sup Yoon1, Thalia Papayannopoulou2, Takayuki Asahara3, Marianne Kearney1, Tina Thorne1, Cynthia Curry1, Liz Eaton1, Lindsay Heyd1, Deepika Dinesh1, Raj Kishore1, Yan Zhu1, and Douglas W. Losordo1

1 Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135
2 Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195
3 Regenerative Medicine and Research, Kobe Institute of Biomedical Research and Innovation/Institute of Physical and Chemical Research, Kobe 650-0047, Japan

CORRESPONDENCE Douglas W. Losordo: Douglas.losordo{at}tufts.edu

The cell surface receptor {alpha}4 integrin plays a critical role in the homing, engraftment, and maintenance of hematopoietic progenitor cells (HPCs) in the bone marrow (BM). Down-regulation or functional blockade of {alpha}4 integrin or its ligand vascular cell adhesion molecule-1 mobilizes long-term HPCs. We investigated the role of {alpha}4 integrin in the mobilization and homing of BM endothelial progenitor cells (EPCs). EPCs with endothelial colony-forming activity in the BM are exclusively {alpha}4 integrin–expressing cells. In vivo, a single dose of anti–{alpha}4 integrin antibody resulted in increased circulating EPC counts for 3 d. In hindlimb ischemia and myocardial infarction, systemically administered anti–{alpha}4 integrin antibody increased recruitment and incorporation of BM EPCs in newly formed vasculature and improved functional blood flow recovery and tissue preservation. Interestingly, BM EPCs that had been preblocked with anti–{alpha}4 integrin ex vivo or collected from {alpha}4 integrin–deficient mice incorporated as well as control cells into the neovasculature in ischemic sites, suggesting that {alpha}4 integrin may be dispensable or play a redundant role in EPC homing to ischemic tissue. These data indicate that functional disruption of {alpha}4 integrin may represent a potential angiogenic therapy for ischemic disease by increasing the available circulating supply of EPCs.

Abbreviations used: Ab, antibody; ß-gal, ß-galactosidase; BMMNC, bone marrow mononuclear cell; BS Bandeiraea simplicifolia; circEPC, circulating endothelial progenitor cell; EC, endothelial cell; EPC, endothelial progenitor cell; FN, fibronectin; HLI, hindlimb ischemia; HPC, hematopoietic progenitor cell; ICAM, intercellular cell adhesion molecule; LAD, left anterior descending; LV, left ventricle; MI, myocardial infarction; PB, peripheral blood; VCAM, vascular cell adhesion molecule.

G. Qin and M. Ii contributed equally to this work.


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