title: Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF.
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.
authors.affiliation: Department of Internal Medicine III, Cardiology and Angiology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Albrecht-Schgoer
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schgoer
authors.forename: Markus
authors.initials: M
authors.lastname: Theurl
authors.forename: Ursula
authors.initials: U
authors.lastname: Stanzl
authors.forename: Daniela
authors.initials: D
authors.lastname: Lener
authors.forename: Daniel
authors.initials: D
authors.lastname: Dejaco
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zelger
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Franz
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002478:Cells, Cultured; D017719:Diabetic Foot / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009479:Neuropeptides / Q000096:biosynthesis*; D010957:Plasmids / Q000235:genetics / Q000494:pharmacology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D053381:Secretogranin II / Q000096:biosynthesis*; D014945:Wound Healing
chemical_list: D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D009479:Neuropeptides; D011509:Proteoglycans; D053381:Secretogranin II; C081159:secretoneurin