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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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