TY - JOUR
T1 - Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1α- and basic FGF-dependent pathway in muscle cells
AU - Egger, Margot
AU - Schgoer, Wilfried
AU - Beer, Arno G.E.
AU - Jeschke, Johannes
AU - Leierer, Johannes
AU - Theurl, Markus
AU - Frauscher, Silke
AU - Tepper, Oren M.
AU - Niederwanger, Andreas
AU - Ritsch, Andreas
AU - Kearney, Marianne
AU - Wanschitz, Julia
AU - Gurtner, Geoffrey C.
AU - Fischer-Colbrie, Reiner
AU - Weiss, Guenter
AU - Piza-Katzer, Hildegunde
AU - Losordo, Douglas W.
AU - Patsch, Josef R.
AU - Schratzberger, Peter
AU - Kirchmair, Rudolf
PY - 2007/9
Y1 - 2007/9
N2 - 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-1α, 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-1α- and basic fibroblast growth factor-dependent mechanisms.
AB - 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-1α, 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-1α- and basic fibroblast growth factor-dependent mechanisms.
KW - Ischemia
KW - Neuropeptides
KW - Vascular biology
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UR - http://www.scopus.com/inward/citedby.url?scp=34548508673&partnerID=8YFLogxK
U2 - 10.1096/fj.06-7440com
DO - 10.1096/fj.06-7440com
M3 - Article
C2 - 17504977
AN - SCOPUS:34548508673
SN - 0892-6638
VL - 21
SP - 2906
EP - 2917
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -