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

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 adenoassociated
virus (rAAV) vectors reduces muscle damage
and promotes muscle regeneration in different
experimental models of muscle necrosis. We demonstrate
that intramuscular administration of rAAVVEGF
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. VEGFtreated
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