title: Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide.
abstract: Endothelial progenitor cells (EPC) are known to contribute to wound healing, but the physiologic triggers for their mobilization are often insufficient to induce complete wound healing in the presence of severe ischemia. EPC trafficking is known to be regulated by hypoxic gradients and induced by vascular endothelial growth factor-mediated increases in bone marrow nitric oxide (NO). Hyperbaric oxygen (HBO) enhances wound healing, although the mechanisms for its therapeutic effects are incompletely understood. It is known that HBO increases nitric oxide levels in perivascular tissues via stimulation of nitric oxide synthase (NOS). Here we show that HBO increases bone marrow NO in vivo thereby increasing release of EPC into circulation. These effects are inhibited by pretreatment with the NOS inhibitor l-nitroarginine methyl ester (l-NAME). HBO-mediated mobilization of EPC is associated with increased lower limb spontaneous circulatory recovery after femoral ligation and enhanced closure of ischemic wounds, and these effects on limb perfusion and wound healing are also inhibited by l-NAME pretreatment. These data show that EPC mobilization into circulation is triggered by hyperoxia through induction of bone marrow NO with resulting enhancement in ischemic limb perfusion and wound healing.
authors.affiliation: Department of Surgery, University of Pennsylvania Medical Center, 4th Floor Silverstein Pavilion, 3400 Spruce Street, Philadelphia, Pennsylvania 19124, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Goldstein
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gallagher
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bauer
authors.forename: Vijay
authors.initials: V
authors.lastname: Baireddy
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Donald G
authors.initials: DG
authors.lastname: Buerk
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.forename: Omaida C
authors.initials: OC
authors.lastname: Velazquez
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000379:methods; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005121:Extremities / Q000098:blood supply / Q000293:injuries; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006931:Hyperbaric Oxygenation; D018496:Hyperoxia / Q000097:blood / Q000503:physiopathology; D007511:Ischemia / Q000628:therapy; D007763:Lac Operon / Q000235:genetics; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
chemical_list: D049452:Green Fluorescent Proteins; D009569:Nitric Oxide