Ang-1 (angiopoietin-1) improves the ineffective angiogenesis and impaired wound healing in diabetes; however, the mechanism underlying this positive effect is still far from being completely understood. In the present study, we investigated whether rAAV (recombinant adeno-associated virus)–Ang-1 gene transfer could improve wound repair in genetically diabetic mice (db+/db+) and the mechanism(s) by which it causes new vessel formation. An incisional skin-wound model in diabetic and normoglycaemic mice was used. After the incision, animals received rAAV–LacZ or rAAV–Ang-1 in the wound edge. After 7 and 14 days, wounds were used to (i) confirm Ang-1 gene transfer, (ii) assess histologically the healing process, (iii) evaluate wound-breaking strength, and (iv) study new vessel formation by PECAM-1 (platelet/endothelial cell adhesion molecule-1) immunostaining. Finally, we investigated VEGF (vascular endothelial growth factor) mRNA and protein levels, eNOS (endothelial NO synthase) expression and VEGFR-1 and VEGFR-2 (VEGF receptor-1 and -2 respectively) immunostaining. The efficiency of Ang-1 gene transfer was confirmed by increased mRNA and protein expression of the protein. rAAV–Ang-1 significantly improved the healing process, stimulating re-epithelization and collagen maturation, increasing breaking strength and significantly augmenting the number of new vessels, as indicated by PECAM-1 immunostaining. However, Ang-1 gene transfer did not modify the decrease in VEGF mRNA and protein expression in diabetic mice; in contrast, Ang-1 increased eNOS expression and augmented nitrate wound content and VEGFR-2 immunostaining and protein expression. Ang-1 gene transfer did not change vascular permeability. Similar results were obtained in normoglycaemic animals. In conclusion, our results provide strong evidence that Ang-1 gene transfer improves the delayed wound repair in diabetes by inducing angiogenesis in a VEGF-independent manner.
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Research Article|
May 14 2008
Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression
Alessandra Bitto;
Alessandra Bitto
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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Letteria Minutoli;
Letteria Minutoli
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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Maria Rosaria Galeano;
Maria Rosaria Galeano
†Department of Surgical Sciences, University of Messina, Messina, Italy
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Domenica Altavilla;
Domenica Altavilla
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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Francesca Polito;
Francesca Polito
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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Tiziana Fiumara;
Tiziana Fiumara
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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Margherita Calò;
Margherita Calò
‡Department of Veterinary Public Health, Section of Veterinary Pharmacology and Toxicology, University of Messina, Messina, Italy
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Patrizia Lo Cascio;
Patrizia Lo Cascio
§Department of Animal Biology and Marine Ecology, Faculty of Science, University of Messina, Messina, Italy
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Lorena Zentilin;
Lorena Zentilin
∥Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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Mauro Giacca;
Mauro Giacca
∥Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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Francesco Squadrito
*Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
Correspondence: Professor Francesco Squadrito (email Francesco.Squadrito@unime.it).
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Publisher: Portland Press Ltd
Received:
July 20 2007
Revision Received:
November 27 2007
Accepted:
December 14 2007
Accepted Manuscript online:
December 14 2007
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2008 Biochemical Society
2008
Clin Sci (Lond) (2008) 114 (12): 707–718.
Article history
Received:
July 20 2007
Revision Received:
November 27 2007
Accepted:
December 14 2007
Accepted Manuscript online:
December 14 2007
Citation
Alessandra Bitto, Letteria Minutoli, Maria Rosaria Galeano, Domenica Altavilla, Francesca Polito, Tiziana Fiumara, Margherita Calò, Patrizia Lo Cascio, Lorena Zentilin, Mauro Giacca, Francesco Squadrito; Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression. Clin Sci (Lond) 1 June 2008; 114 (12): 707–718. doi: https://doi.org/10.1042/CS20070250
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