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Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1- and basic FGF-dependent pathway in muscle cells

Margot Egger^*, Wilfried Schgoer^*, Arno G. E. Beer^*, Johannes Jeschke, Johannes Leierer, Markus Theurl^*, Silke Frauscher^*, Oren M. Tepper^||, Andreas Niederwanger^*, Andreas Ritsch^*, Marianne Kearney^¶, Julia Wanschitz, Geoffrey C. Gurtner^||, Reiner Fischer-Colbrie, Guenter Weiss^*, Hildegunde Piza-Katzer, Douglas W. Losordo^¶,, Josef R. Patsch^*, Peter Schratzberger^* and Rudolf Kirchmair^*,1

^* Department of Internal Medicine, General Internal Medicine,

Department of Neurology,

Department of Plastic Surgery, and

Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria;

^|| The Laboratory of Microvascular Research and Vascular Tissue Engineering, New York University Medical Center, New York, New York, USA; and

^¶ Division of Cardiovascular Research and

Vascular Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

¹Correspondence: Department of Internal Medicine, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria. E-mail: rudolf.kirchmair{at}uibk.ac.at

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-1, 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-1- and basic fibroblast growth factor-dependent mechanisms.—Egger, M., Schgoer, W., Beer, A. G. E., Jeschke, J., Leierer, J., Theurl, M., Frauscher, S., Tepper, O. M., Niederwanger, A., Ritsch, A., Kearney, M., Wanschitz, J., Gurtner, G. C., Fischer-Colbrie, R., Weiss, G., Piza-Katzer, H., Losordo, D. W., Patsch, J. R., Schratzberger, P., Kirchmair, R. Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1- and basic FGF-dependent pathway in muscle cells.

Key Words: vascular biology • neuropeptides • ischemia