title: Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization.
abstract: 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.
authors.affiliation: Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Andrea
authors.initials: A
authors.lastname: Wecker
authors.forename: Evelyn
authors.initials: E
authors.lastname: Bord
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Mary
authors.initials: M
authors.lastname: Gavin
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
authors.forename: Young-sup
authors.initials: YS
authors.lastname: Yoon
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.forename: Liz
authors.initials: L
authors.lastname: Eaton
authors.forename: Lindsay
authors.initials: L
authors.lastname: Heyd
authors.forename: Deepika
authors.initials: D
authors.lastname: Dinesh
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: 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*
chemical_list: D039441:Integrin alpha4