Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy.,PLOS Genetics

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Inhibition of FLT1 ameliorates muscular dystrophy phenotype by increased vasculature in a mouse model of Duchenne muscular dystrophy.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-26 , DOI: 10.1371/journal.pgen.1008468
Mayank Verma _{1,

2,

3,

4} , Yuko Shimizu-Motohashi _{2,

3,

4} , Yoko Asakura _{2,

3,

4} , James P Ennen _{2,

3,

4} , Jennifer Bosco ₅ , Zhiwei Zhou ₅ , Guo-Hua Fong ₆ , Serene Josiah ₅ , Dennis Keefe ₅ , Atsushi Asakura _{2,

3,

4}

Affiliation

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.

中文翻译：

在Duchenne肌肉营养不良的小鼠模型中，FLT1的抑制通过增加脉管系统改善了肌肉营养不良的表型。

Duchenne肌营养不良症（DMD）是X连锁隐性遗传病，其中编码膜稳定蛋白的肌营养不良蛋白发生突变。最近，脉管系统还显示出在DMD和DMD模型mdx小鼠中受到干扰。最近的DMD转录组学揭示了缺陷与血管内皮生长因子（VEGF）信号通路相关。为了揭示DMD和VEGF信号传导之间的关系，将mdx小鼠与组成型（CAGCreERTM：Flt1LoxP / LoxP）和内皮细胞特异性条件基因敲除小鼠（Cdh5CreERT2：Flt1LoxP / LoxP）杂交，以作为Flt1（VEGFR1）的诱饵受体。血管内皮生长因子。在这里，我们发现，虽然Flt1的组成型缺失不利于骨骼肌功能，但内皮细胞特异性Flt1缺失却导致血管密度增加，增加了mdx小鼠的卫星细胞数量并改善了DMD相关表型。在给予抗FLT1肽或单克隆抗体可阻断VEGF-FLT1结合的mdx小鼠中，概括了这些病理学上的下降，包括改善的肌肉组织学和功能。FLT1阻断可改善营养不良性肌的组织学和功能，为潜在治疗DMD提供了新的药理策略。

更新日期：2019-12-27

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