Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy


Autoři: Mayank Verma aff001;  Yuko Shimizu-Motohashi aff002;  Yoko Asakura aff002;  James P. Ennen aff002;  Jennifer Bosco aff005;  Zhiwei Zhou aff005;  Guo-Hua Fong aff006;  Serene Josiah aff005;  Dennis Keefe aff005;  Atsushi Asakura aff002
Působiště autorů: Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN, United States of America aff001;  Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, United States of America aff002;  Paul & Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, United States of America aff003;  Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America aff004;  Shire Human Genetic Therapies, Inc., a member of the Takeda group of companies, Lexington, MA, United States of America aff005;  Center for Vascular Biology, University of Connecticut Health Center, University of Connecticut School of Medicine, Farmington, CT, United States of America aff006
Vyšlo v časopise: Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. PLoS Genet 15(12): e1008468. doi:10.1371/journal.pgen.1008468
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008468

Souhrn

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease in which the dystrophin coding for a membrane stabilizing protein is mutated. Recently, the vasculature has also shown to be perturbed in DMD and DMD model mdx mice. Recent DMD transcriptomics revealed the defects were correlated to a vascular endothelial growth factor (VEGF) signaling pathway. To reveal the relationship between DMD and VEGF signaling, mdx mice were crossed with constitutive (CAGCreERTM:Flt1LoxP/LoxP) and endothelial cell-specific conditional gene knockout mice (Cdh5CreERT2:Flt1LoxP/LoxP) for Flt1 (VEGFR1) which is a decoy receptor for VEGF. Here, we showed that while constitutive deletion of Flt1 is detrimental to the skeletal muscle function, endothelial cell-specific Flt1 deletion resulted in increased vascular density, increased satellite cell number and improvement in the DMD-associated phenotype in the mdx mice. These decreases in pathology, including improved muscle histology and function, were recapitulated in mdx mice given anti-FLT1 peptides or monoclonal antibodies, which blocked VEGF-FLT1 binding. The histological and functional improvement of dystrophic muscle by FLT1 blockade provides a novel pharmacological strategy for the potential treatment of DMD.

Klíčová slova:

Body weight – Enzyme-linked immunoassays – Mouse models – Muscle fibers – Muscle functions – Skeletal muscles – Duchenne muscular dystrophy – Skeletal muscle fibers


Zdroje

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