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Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF

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Abstract

Diabetic foot ulcers represent a therapeutic problem of high clinical relevance. Reduced vascular supply, neuropathy and diminished expression of growth factors strongly contribute to wound healing impairment in diabetes. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas. Therefore, topical secretoneurin gene therapy was tested in a full thickness wound healing model in diabetic db/db mice. Secretoneurin significantly accelerated wound closure in these mice and immunohistochemistry revealed higher capillary and arteriole density in the wounded area compared to control mice. In-vitro, the mechanism of action of secretoneurin on human dermal microvascular endothelial cells was evaluated in normal and diabetic cells. Secretoneurin shows positive effects on in vitro angiogenesis, proliferation and apoptosis of these cells in a basic fibroblast growth factor dependent manner. A small molecular weight inhibitor revealed fibroblast growth factor receptor 3 as the main receptor for secretoneurin mediated effects. Additionally, we could identify heparan-sulfates as important co-factor of secretoneurin induced binding of basic fibroblast growth factor to human dermal endothelial cells. We suggest topical secretoneurin plasmid therapy as new tool for delayed wound healing in patients suffering from diabetes.

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Acknowledgments

We would like to thank Birgit Moser from the Department of Dermatology and Venereology at the Medical University of Innsbruck for help with immunohistochemical analysis.

Ethical standards

All experiments within this manuscript comply with the current laws of Austria.

Conflict of interest

There is no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine III, Cardiology and Angiology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    Karin Albrecht-Schgoer, Wilfried Schgoer, Markus Theurl, Ursula Stanzl, Daniela Lener, Daniel Dejaco, Wolfgang M. Franz & Rudolf Kirchmair

  2. Department of Dermatology and Venereology, Medical University Innsbruck, Innsbruck, Austria

    Bernhard Zelger

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  1. Karin Albrecht-Schgoer
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  2. Wilfried Schgoer
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  9. Rudolf Kirchmair
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Correspondence to Rudolf Kirchmair.

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Albrecht-Schgoer, K., Schgoer, W., Theurl, M. et al. Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF. Angiogenesis 17, 27–36 (2014). https://doi.org/10.1007/s10456-013-9375-4

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  • DOI: https://doi.org/10.1007/s10456-013-9375-4

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