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(Circulation Research. 2009;105:994.)
© 2009 American Heart Association, Inc.

Integrative Physiology

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

Wilfried Schgoer, Markus Theurl, Johannes Jeschke, Arno G.E. Beer, Karin Albrecht, Roland Gander, Song Rong, Danijela Vasiljevic, Margot Egger, Anna Maria 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

From the Department of Internal Medicine (W.S., M.T., A.G.E.B., K.A., R.G., D.V., M.E., S.F., B.K., I.T., J.R.P., P.S., A.R., R.K.), Internal Medicine 1; Tyrolean Cancer Research Institute (A.M.W., D.W.), Internal Medicine 5; and Departments of Plastic Surgery (J.J., H.P.-K.) and Pharmacology (R.F.-C.), Medical University of Innsbruck, Austria; Department of Nephrology (S.R.), Hannover Medical School, Germany; and Klinik für Innere Medizin IV (F.H.B), Universitätsklinikum des Saarlandes, Germany.

Correspondence to Rudolf Kirchmair, MD, Associate Professor of Medicine, Department of Internal Medicine 1, Medical University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria. E-mail rudolf.kirchmair{at}i-med.ac.at

Rationale: The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells.

Objective: We sought to investigate the effects of secretoneurin on therapeutic angiogenesis.

Methods and Results: 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.

Conclusions: 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.

Key Words: angiogenesis • endothelium • gene therapy • hypoxia • peripheral vascular disease