title: Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1alpha- and basic FGF-dependent pathway in muscle cells.
abstract: Expression of angiogenic cytokines like vascular endothelial growth factor is enhanced by hypoxia. We tested the hypothesis that decreased oxygen levels up-regulate the angiogenic factor secretoneurin. In vivo, muscle cells of mouse ischemic hind limbs showed increased secretoneurin expression, and inhibition of secretoneurin by a neutralizing antibody impaired the angiogenic response in this ischemia model. In a mouse soft tissue model of hypoxia, secretoneurin was increased in subcutaneous muscle fibers. In vitro, secretoneurin mRNA and protein were up-regulated in L6 myoblast cells after exposure to low oxygen levels. The hypoxia-dependent regulation of secretoneurin was tissue specific and was not observed in endothelial cells, vascular smooth muscle cells, or AtT20 pituitary tumor cells. The hypoxia-dependent induction of secretoneurin in L6 myoblasts is regulated by hypoxia-inducible factor-1alpha, since inhibition of this factor using si-RNA inhibited up-regulation of secretoneurin. Induction of secretoneurin by hypoxia was dependent on basic fibroblast growth factor in vivo and in vitro, and inhibition of this regulation by heparinase suggests an involvement of low-affinity basic fibroblast growth factor binding sites. In summary, our data show that the angiogenic cytokine secretoneurin is up-regulated by hypoxia in muscle cells by hypoxia-inducible factor-1alpha- and basic fibroblast growth factor-dependent mechanisms.
authors.affiliation: Department of Internal Medicine, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
authors.forename: Margot
authors.initials: M
authors.lastname: Egger
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schgoer
authors.forename: Arno G E
authors.initials: AG
authors.lastname: Beer
authors.forename: Johannes
authors.initials: J
authors.lastname: Jeschke
authors.forename: Johannes
authors.initials: J
authors.lastname: Leierer
authors.forename: Markus
authors.initials: M
authors.lastname: Theurl
authors.forename: Silke
authors.initials: S
authors.lastname: Frauscher
authors.forename: Oren M
authors.initials: OM
authors.lastname: Tepper
authors.forename: Andreas
authors.initials: A
authors.lastname: Niederwanger
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritsch
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Julia
authors.initials: J
authors.lastname: Wanschitz
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
authors.forename: Reiner
authors.initials: R
authors.lastname: Fischer-Colbrie
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
authors.forename: Hildegunde
authors.initials: H
authors.lastname: Piza-Katzer
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Josef R
authors.initials: JR
authors.lastname: Patsch
authors.forename: Peter
authors.initials: P
authors.lastname: Schratzberger
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005121:Extremities / Q000601:surgery; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D043484:Proprotein Convertases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D053381:Secretogranin II / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D017931:DNA Primers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009479:Neuropeptides; D034741:RNA, Small Interfering; D053381:Secretogranin II; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009243:NAD; D016222:Fibroblast Growth Factor 2; C081159:secretoneurin; C513086:Pcsk6 protein, mouse; D043484:Proprotein Convertases