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

Mayank Verma, Yuko Shimizu-Motohashi, Yoko Asakura, James P. Ennen, Jennifer Bosco, Zhiwei Zhou, Guo Hua Fong, Serene Josiah, Dennis Keefe, Atsushi Asakura

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere1008468
JournalPLoS genetics
Volume15
Issue number12
DOIs
StatePublished - Jan 1 2019

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PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Verma, M., Shimizu-Motohashi, Y., Asakura, Y., Ennen, J. P., Bosco, J., Zhou, Z., Fong, G. H., Josiah, S., Keefe, D., & Asakura, A. (2019). Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. PLoS genetics, 15(12), [e1008468]. https://doi.org/10.1371/journal.pgen.1008468