Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization.
The cell surface receptor alpha4 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 alpha4 integrin or its ligand vascular cell adhesion molecule-1 mobilizes long-term HPCs. We investigated the role of alpha4 integrin in the mobilization and homing of BM endothelial progenitor cells (EPCs). EPCs with endothelial colony-forming activity in the BM are exclusively alpha4 integrin-expressing cells. In vivo, a single dose of anti-alpha4 integrin antibody resulted in increased circulating EPC counts for 3 d. In hindlimb ischemia and myocardial infarction, systemically administered anti-alpha4 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-alpha4 integrin ex vivo or collected from alpha4 integrin-deficient mice incorporated as well as control cells into the neovasculature in ischemic sites, suggesting that alpha4 integrin may be dispensable or play a redundant role in EPC homing to ischemic tissue. These data indicate that functional disruption of alpha4 integrin may represent a potential angiogenic therapy for ischemic disease by increasing the available circulating supply of EPCs.
Qin
Gangjian
G
Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135.
Ii
Masaaki
M
Silver
Marcy
M
Wecker
Andrea
A
Bord
Evelyn
E
Ma
Hong
H
Gavin
Mary
M
Goukassian
David A
DA
Yoon
Young-sup
YS
Papayannopoulou
Thalia
T
Asahara
Takayuki
T
Kearney
Marianne
M
Thorne
Tina
T
Curry
Cynthia
C
Eaton
Liz
L
Heyd
Lindsay
L
Dinesh
Deepika
D
Kishore
Raj
R
Zhu
Yan
Y
Losordo
Douglas W
DW
D000818:Animals; D001853:Bone Marrow; D002465:Cell Movement; D042783:Endothelial Cells; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000503:physiopathology*; D018919:Neovascularization, Physiologic; D013234:Stem Cells / Q000502:physiology*
D039441:Integrin alpha4