title: Effect of vascular endothelial growth factor gene therapy on post-traumatic peripheral nerve regeneration and denervation-related muscle atrophy.
abstract: Functional recovery after peripheral nerve injury depends on both improvement of nerve regeneration and prevention of denervation-related skeletal muscle atrophy. To reach these goals, in this study we overexpressed vascular endothelial growth factor (VEGF) by means of local gene transfer with adeno-associated virus (AAV). Local gene transfer in the regenerating peripheral nerve was obtained by reconstructing a 1-cm-long rat median nerve defect using a vein segment filled with skeletal muscle fibers that have been previously injected with either AAV2-VEGF or AAV2-LacZ, and the morphofunctional outcome of nerve regeneration was assessed 3 months after surgery. Surprisingly, results showed that overexpression of VEGF in the muscle-vein-combined guide led to a worse nerve regeneration in comparison with AAV-LacZ controls. Local gene transfer in the denervated muscle was obtained by direct injection of either AAV2-VEGF or AAV2-LacZ in the flexor digitorum sublimis muscle after median nerve transection and results showed a significantly lower progression of muscle atrophy in AAV2-VEGF-treated muscles in comparison with muscles treated with AAV2-LacZ. Altogether, our results suggest that local delivery of VEGF by AAV2-VEGF-injected transplanted muscle fibers do not represent a rational approach to promote axonal regeneration along a venous nerve guide. By contrast, AAV2-VEGF direct local injection in denervated skeletal muscle significantly attenuates denervation-related atrophy, thus representing a promising strategy for improving the outcome of post-traumatic neuromuscular recovery after nerve injury and repair.
authors.affiliation: 1] Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy [2] Department of Medical Sciences, Faculty of Medicine, University of Trieste, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Moimas
authors.forename: F
authors.initials: F
authors.lastname: Novati
authors.forename: G
authors.initials: G
authors.lastname: Ronchi
authors.forename: S
authors.initials: S
authors.lastname: Zacchigna
authors.forename: F
authors.initials: F
authors.lastname: Fregnan
authors.forename: L
authors.initials: L
authors.lastname: Zentilin
authors.forename: G
authors.initials: G
authors.lastname: Papa
authors.forename: M
authors.initials: M
authors.lastname: Giacca
authors.forename: S
authors.initials: S
authors.lastname: Geuna
authors.forename: I
authors.initials: I
authors.lastname: Perroteau
authors.forename: Z M
authors.initials: ZM
authors.lastname: Arnež
authors.forename: S
authors.initials: S
authors.lastname: Raimondo
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal; D009133:Muscular Atrophy / Q000473:pathology / Q000628:therapy*; D009416:Nerve Regeneration; D059348:Peripheral Nerve Injuries / Q000628:therapy; D010525:Peripheral Nerves / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat