Gene therapy with the angiogenic cytokine secretoneurin induces therapeutic angiogenesis by a nitric oxide-dependent mechanism.
BACKGROUND
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.


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.
Department of Internal Medicine 1, Medical University of Innsbruck, Austria.
Wilfried
W
Schgoer
Markus
M
Theurl
Johannes
J
Jeschke
Arno G E
AG
Beer
Karin
K
Albrecht
Roland
R
Gander
Song
S
Rong
Danijela
D
Vasiljevic
Margot
M
Egger
Anna Maria
AM
Wolf
Silke
S
Frauscher
Bernhard
B
Koller
Ivan
I
Tancevski
Josef R
JR
Patsch
Peter
P
Schratzberger
Hildegunde
H
Piza-Katzer
Andreas
A
Ritsch
Ferdinand H
FH
Bahlmann
Reiner
R
Fischer-Colbrie
Dominik
D
Wolf
Rudolf
R
Kirchmair
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D053381:Secretogranin II / Q000096:biosynthesis* / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D016207:Cytokines; D009479:Neuropeptides; D053381:Secretogranin II; C081159:secretoneurin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse