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

English version

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): e32767. doi:10.1371/journal.pgen.1008468
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/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 (CAG^CreERTM:Flt1^LoxP/LoxP) and endothelial cell-specific conditional gene knockout mice (Cdh5^CreERT2:Flt1^LoxP/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 – Mouse models – Enzyme-linked immunoassays – Skeletal muscles – Muscle functions – Muscle fibers – Duchenne muscular dystrophy – Skeletal muscle fibers

Zdroje

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