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.

The sciatic nerve injury model in pre-clinical research

“…Therefore, while SNI is not suitable to study the effects of chronic denervation on the sensory function, this experimental model is, by contrast, a very useful approach for the study of denervation of the distal nerve trunk and the skeletal muscles as well as the sought of effective strategies to prevent it (Russo et al, 2007;Saito et al, 2009;Karsidag et al, 2012;Moimas et al, 2013;Blom et al, 2014).…”

Regeneración de las lesiones críticas del nervio periférico con factores de crecimiento. Estudio experimental

“…Con este proyecto de investigación, hemos intentado avanzar en la línea ya iniciada en investigaciones previas de nuestro grupo de trabajo, en búsqueda de diferentes formas de presentar el injerto muscular como puente en las lesiones críticas nerviosas, y las opciones de las que disponemos para enriquecerlo biológicamente, apoyando nuestro proyecto en las actuales experimentaciones con factores de crecimiento (Gordon T, 2009;Yu et al, 2009;Moimas et al, 2013).…”

“…Estos hallazgos están en consonancia con lo publicado previamente: Moimas et al, 2013 analiza la atrofia muscular al mes de la reparación de la lesión, en su caso, con el depósito local de VEGF.…”

“…Así, Gravvanis et al, describen la recuperación de la deambulación al rellenar un injerto de vena con NGF (Gravvanis et al, 2004); Pfister et al, analizan los diferentes factores de crecimiento utilizados en la actualidad y su incorporación en conductos nerviosos sintéticos de materiales biodegradables (Pfister et al, 2007); Moimas et al, con VEGF o factor de crecimiento del endotelio vascular, en un injerto de vena relleno de fibras de músculo estriado tratadas químicamente con anterioridad a su implantación (Moimas et al, 2013); o Mohammadi et al, empleando IGF-1 como promotor de la regeneración del defecto nervioso cubierto con un injerto arterial (Mohammadi et al, 2013).…”

“…El músculo ha sido descrito como la estructura histológica más eficaz para la liberación local de los factores en él inyectados (Giacca M, 2007;Moimas et al, 2013).…”