Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo.
Vascular endothelial growth factor (VEGF) is a major regulator of blood vessel formation during development and in the adult organism. Recent evidence indicates that this factor also plays an important role in sustaining the proliferation and differentiation of different cell types, including progenitor cells of different tissues, including bone marrow, bone, and the central nervous system. Here we show that the delivery of the 165-aa isoform of VEGF-A cDNA using an adeno-associated virus (AAV) vector exerts a powerful effect on skeletal muscle regeneration in vivo. Following ischemia-, glycerol-, or cardiotoxin-induced damage in mouse skeletal muscle, the delivery of AAV-VEGF markedly improved muscle fiber reconstitution with a dose-dependent effect. The expression of both VEGF receptor-1 (VEGFR-1) and VEGFR-2 was upregulated both in the satellite cells of the damaged muscles and during myotube formation in vitro; the VEGF effect was mediated by the VEGFR-2, since the transfer of PlGF, a VEGF family member interacting with the VEGFR-1, was ineffective. These results are consistent with the observation that VEGF promotes the growth of myogenic fibers and protects the myogenic cells from apoptosis in vitro and prompt a therapeutic use for VEGF gene transfer in a variety of muscular disorders.
Arsic
Nikola
N
Molecular Medicine Laboratory, International Center for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
Zacchigna
Serena
S
Zentilin
Lorena
L
Ramirez-Correa
Genaro
G
Pattarini
Lucia
L
Salvi
Alessandro
A
Sinagra
Gianfranco
G
Giacca
Mauro
M
D000818:Animals; D017209:Apoptosis; D003603:Cytotoxins / Q000633:toxicity; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005990:Glycerol / Q000633:toxicity; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D032446:Myoblasts / Q000737:chemistry / Q000502:physiology; D009336:Necrosis; D012038:Regeneration; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000502:physiology
D003603:Cytotoxins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D005990:Glycerol