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

• DOI: 10.1371/journal.pgen.1008468
• Publication Date: 2019-12-26T18:26:16Z
• Authors: Mayank Verma; Yuko Shimizu-Moto...; Yoko Asakura; James P. Ennen; Jennifer Bosco; Zhiwei Zhou; Guo-Hua Fong; Serene Josiah; Dennis Keefe; Atsushi Asakura
• Keywords: Male; Vascular Endothelial Growth Factor A; 0301 basic medicine; Vascular Endothelial Growth Factor Receptor-1; Antibodies, Monoclonal; Endothelial Cells; QH426-470; 3. Good health; Muscular Dystrophy, Duchenne; Disease Models, Animal; Gene Knockout Techniques; Mice; 03 medical and health sciences; Organ Specificity; Genetics; Mice, Inbred mdx; Animals; Muscle, Skeletal; Peptides; Research Article; Signal Transduction

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.