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Gene Therapy With the Angiogenic Cytokine Secretoneurin Induces Therapeutic Angiogenesis by a Nitric Oxide–Dependent Mechanism

2009; Lippincott Williams & Wilkins; Volume: 105; Issue: 10 Linguagem: Inglês

10.1161/circresaha.109.199513

1524-4571

Wilfried Schgoer, Markus Theurl, Johannes Jeschke, Arno Beer, Karin Albrecht-Schgoer, Roland Gander, Song Rong, Danijela Vasiljevic, Margot Egger, Anna Wolf, Silke Frauscher, Bernhard Koller, Ivan Tancevski, Josef R. Patsch, Peter Schratzberger, Hildegunde Piza‐Katzer, Andreas Ritsch, Ferdinand H. Bahlmann, Reiner Fischer‐Colbrie, Dominik Wolf, Rudolf Kirchmair,

Cancer, Hypoxia, and Metabolism

The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells.We sought to investigate the effects of secretoneurin on therapeutic angiogenesis.We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells.In summary, our data indicate that gene therapy with secretoneurin induces therapeutic angiogenesis, arteriogenesis, and vasculogenesis in the hindlimb ischemia model by a nitric oxide-dependent mechanism.