title: Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding.
abstract: Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that controls vascular responses to hypoxia and ischemia. In this study, mice that were heterozygous (HET) for a null allele at the locus encoding the HIF-1alpha subunit (HET mice) and their wild-type (WT) littermates were subjected to a thermal injury involving 10% of the body surface area. HIF-1alpha protein levels were increased in burn wounds of WT but not of HET mice on day 2. The serum levels of stromal-derived factor 1alpha, which binds to CXCR4, were increased on day 2 in WT but not in HET mice. Circulating angiogenic cells were also increased on day 2 in WT but not in HET mice and included CXCR4(+)Sca1(+) cells. Laser Doppler perfusion imaging demonstrated increased blood flow in burn wounds of WT but not HET mice on day 7. Immunohistochemistry on day 7 revealed a reduced number of CD31(+) vessels at the healing margin of burn wounds in HET as compared with WT mice. Vessel maturation was also impaired in wounds of HET mice as determined by the number of alpha-smooth muscle actin-positive vessels on day 21. The remaining wound area on day 14 was significantly increased in HET mice compared with WT littermates. The percentage of healed wounds on day 14 was significantly decreased in HET mice. These data delineate a signaling pathway by which HIF-1 promotes angiogenesis during burn wound healing.
authors.affiliation: Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Xianjie
authors.initials: X
authors.lastname: Zhang
authors.forename: Lixin
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wei
authors.forename: Yee Sun
authors.initials: YS
authors.lastname: Tan
authors.forename: Lana
authors.initials: L
authors.lastname: Tong
authors.forename: Ryan
authors.initials: R
authors.lastname: Chang
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Ghanamah
authors.forename: Maura
authors.initials: M
authors.lastname: Reinblatt
authors.forename: Guy P
authors.initials: GP
authors.lastname: Marti
authors.forename: John W
authors.initials: JW
authors.lastname: Harmon
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D002056:Burns / Q000378:metabolism*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000097:blood; D006579:Heterozygote; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D017078:Laser-Doppler Flowmetry; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000378:metabolism; D012039:Regional Blood Flow; D014945:Wound Healing
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4