Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1alpha- and basic FGF-dependent pathway in muscle cells.
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.
Egger
Margot
M
Department of Internal Medicine, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
Schgoer
Wilfried
W
Beer
Arno G E
AG
Jeschke
Johannes
J
Leierer
Johannes
J
Theurl
Markus
M
Frauscher
Silke
S
Tepper
Oren M
OM
Niederwanger
Andreas
A
Ritsch
Andreas
A
Kearney
Marianne
M
Wanschitz
Julia
J
Gurtner
Geoffrey C
GC
Fischer-Colbrie
Reiner
R
Weiss
Guenter
G
Piza-Katzer
Hildegunde
H
Losordo
Douglas W
DW
Patsch
Josef R
JR
Schratzberger
Peter
P
Kirchmair
Rudolf
R
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
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