Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice

Mayank Verma, Yoko Asakura, Hiroyuki Hirai, Shuichi Watanabe, Christopher Tastad, Guo Hua Fong, Masatsugu Ema, Jarrod A. Call, Dawn A. Lowe, Atsushi Asakura

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the developmental relationship between muscular dystrophy and vasculature, mdx mice, an animal model for DMD, were crossed with Flt-1 gene knockout mice to create a model with increased vasculature. Flt-1 is a decoy receptor for vascular endothelial growth factor, and therefore both homozygous (Flt-1-/-) and heterozygous (Flt-1+/-) Flt-1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show that Flt-1+/- and mdx:Flt-1+/- adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice, respectively. The mdx:Flt-1+/- mice show improved muscle histology compared with the mdx mice with decreased fibrosis, calcification and membrane permeability. Functionally, the mdx:Flt-1+/- mice have an increase in muscle blood flow and force production, compared with the mdx mice. Consequently, the mdx:utrophin-/-:Flt-1+/- mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin-/- mice, which show more severe muscle phenotypes than the mdx mice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease.

Original languageEnglish (US)
Article numberddq334
Pages (from-to)4145-4159
Number of pages15
JournalHuman molecular genetics
Volume19
Issue number21
DOIs
StatePublished - Aug 12 2010

Bibliographical note

Funding Information:
This work was supported by the Undergraduate Research Opportunity Program (637-5904 to M.V.); the Gregory Marzolf Muscular Dystrophy Training Grant (06378016 to M.V.); NIH P30 grant (P30AR057220 to D.A.L.) for supplying the mdx:utrn2/2 mice, and the Muscular Dystrophy Association (MDA69856 to A.A.).

Fingerprint Dive into the research topics of 'Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice'. Together they form a unique fingerprint.

Cite this