Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy.
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 correl...
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Public Library of Science (PLoS)
2019-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008468&type=printable |
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| author | Mayank Verma Yuko Shimizu-Motohashi Yoko Asakura James P Ennen Jennifer Bosco Zhiwei Zhou Guo-Hua Fong Serene Josiah Dennis Keefe Atsushi Asakura |
| author_facet | Mayank Verma Yuko Shimizu-Motohashi Yoko Asakura James P Ennen Jennifer Bosco Zhiwei Zhou Guo-Hua Fong Serene Josiah Dennis Keefe Atsushi Asakura |
| author_sort | Mayank Verma |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e43f9db685584f0ead194a9b1ef89670 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-e43f9db685584f0ead194a9b1ef896702025-08-20T02:54:53ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-12-011512e100846810.1371/journal.pgen.1008468Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy.Mayank VermaYuko Shimizu-MotohashiYoko AsakuraJames P EnnenJennifer BoscoZhiwei ZhouGuo-Hua FongSerene JosiahDennis KeefeAtsushi AsakuraDuchenne 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008468&type=printable |
| spellingShingle | Mayank Verma Yuko Shimizu-Motohashi Yoko Asakura James P Ennen Jennifer Bosco Zhiwei Zhou Guo-Hua Fong Serene Josiah Dennis Keefe Atsushi Asakura Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. PLoS Genetics |
| title | Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. |
| title_full | Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. |
| title_fullStr | Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. |
| title_full_unstemmed | Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. |
| title_short | Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy. |
| title_sort | inhibition of flt1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of duchenne muscular dystrophy |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008468&type=printable |
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