Angiopoietin-1 gene transfer improves the impaired wound healing of the genetically diabetic mice without increasing VEGF expression
Résumé
Angiopoietin-1 improves the ineffective angiogenesis and the impaired wound healing of diabetes. However the mechanism underlying this positive effect is still far from being completely understood. We investigated whether rAAV-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 on diabetic and normoglycaemic mice was used. After the incision in the wound edge animals received rAAV-Lac-Z or rAAV-Ang-1. After 7 and 14 days wounds were used to confirm Ang-1 gene transfer, to assess histologically the healing process, to evaluate wound breaking strength, and to study new vessel formation by PECAM-1 (platelet/endothelial cell adhesion molecule) immunostaining. Finally we investigated VEGF-mRNA and protein content, eNOS expression and VEGFR-1 and VEGFR-2 immunostaining. The efficiency of Ang-1 gene transfer was confirmed by its increased mRNA and protein expression. rAAV-Ang-1 significantly improved the healing process stimulating reepithelization and collagen maturation, increased breaking strength and significantly augmented the number of new vessels, as indicated by PECAM-1 immunostaining. However Ang-1 gene transfer did not modify the deficient VEGF-mRNA and protein expression in diabetic mice; in contrast it increased eNOS expression, augmented nitrate wound content and VEGFR-2 immunostaining and protein expression. rAAV-Ang-1 did not change vascular permeability. Similar results were obtained in normoglycaemic animals. Our data provide strong evidence that Ang-1 gene transfer improves the delayed wound repair in diabetes by inducing angiogenesis in a VEGF-independent manner.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...