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.
Schgoer
Wilfried
W
Department of Internal Medicine 1, Medical University of Innsbruck, Austria.
Theurl
Markus
M
Jeschke
Johannes
J
Beer
Arno G E
AG
Albrecht
Karin
K
Gander
Roland
R
Rong
Song
S
Vasiljevic
Danijela
D
Egger
Margot
M
Wolf
Anna Maria
AM
Frauscher
Silke
S
Koller
Bernhard
B
Tancevski
Ivan
I
Patsch
Josef R
JR
Schratzberger
Peter
P
Piza-Katzer
Hildegunde
H
Ritsch
Andreas
A
Bahlmann
Ferdinand H
FH
Fischer-Colbrie
Reiner
R
Wolf
Dominik
D
Kirchmair
Rudolf
R
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