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VEGF overexpression via adeno-associated virus gene transfer promotes skeletal muscle regeneration and enhances muscle function in mdx mice

Sonia Messina^*, Anna Mazzeo^*, Alessandra Bitto, M’hammed Aguennouz^*, Alba Migliorato^*, Maria G. De Pasquale^*, Letteria Minutoli, Domenica Altavilla, Lorena Zentilin, Mauro Giacca^,, Francesco Squadrito and Giuseppe Vita^*,1

^* Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy;

Department of Experimental Medicine and Pharmacology, University of Messina, Messina, Italy;

Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; and

Department of Clinical and Biomedical Science, Faculty of Medicine, University of Trieste, Italy

¹Correspondence: Department of Neurosciences, Psychiatry and Anaesthesiology, Unit of Clinical Neurobiology and Neuromuscular Diseases, AOU Policlinico "G. Martino," 98125 Messina, Italy. E-mail: giuseppe.vita{at}unime.it

Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis. Recently it was reported that the delivery of VEGF using recombinant adeno-associated virus (rAAV) vectors reduces muscle damage and promotes muscle regeneration in different experimental models of muscle necrosis. We demonstrate that intramuscular administration of rAAV-VEGF improved pathophysiology of the mdx mouse, a model of Duchenne muscular dystrophy (DMD). One month after injection, rAAV-VEGF-treated muscles showed augmented expression of VEGF and immunolocalization of its receptor, VEGFR-2. VEGF-treated mdx mice showed increased forelimb strength and strength normalized to weight. Treatment reduced necrotic fibers area and increased regenerating fibers area with an augmented number of myogenin-positive satellite cells and myonuclei, and of developmental myosin heavy chain-positive fibers. Only the regenerating area showed increased capillary density. This study provides novel evidence of a VEGF beneficial effect in mdx mice that is exerted mainly by a proregenerative and angiogenic effect. It opens new therapeutic prospectives in DMD and other types of muscular disorders.—Messina, S., Mazzeo, A., Bitto, A., Aguennouz, M., Migliorato, A., De Pasquale, M. G., Minutoli, L., Altavilla, D., Zentilin, L., Giacca, M., Squadrito, F., Vita, G. VEGF overexpression via adeno-associated virus gene transfer promotes skeletal muscle regeneration and enhances muscle function in mdx mice.

Key Words: dystrophin gene • muscle necrosis • rAAV • Duchenne muscular dystrophy

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