Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice.
Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice.
复制标题
Flt-1 单倍体不足通过 mdx 小鼠中脉管系统的发育增加改善肌营养不良表型。
DOI：
10.1093/hmg/ddq334
复制
发表时间：
2010
影响因子：
3.5
通讯作者：
Asakura,Atsushi
中科院分区：
文献类型：
--
作者：
Verma,Mayank;Asakura,Yoko;Hirai,Hiroyuki;Watanabe,Shuichi;Tastad,Christopher;Fong,Guo-Hua;Ema,Masatsugu;Call,JarrodA;Lowe,DawnA;Asakura,Atsushi
杜氏肌营养不良症（DMD）是一种X连锁隐性遗传疾病，由编码蛋白质肌营养不良蛋白的基因突变引起。最近的工作表明，肌营养不良蛋白也被发现在脉管系统和它的缺乏导致血管缺陷和异常血流。这诱导了进一步加重肌营养不良症发病机制的缺血状态。对于DMD的有效治疗形式，需要解决肌肉和血管两者。为了揭示肌营养不良与血管发育的关系，将DMD动物模型mdx小鼠与Flt-1基因敲除小鼠杂交，以建立血管增加的模型。Flt-1是血管内皮生长因子的诱饵受体，因此Flt-1基因敲除的纯合子（Flt-1−/−）和杂合子（Flt-1+/−）小鼠在胚胎发生期间均显示内皮细胞增殖和血管密度增加。在这里，我们发现Flt-1+/−和mdx：Flt-1+/−成年小鼠也显示出骨骼肌血管密度的发育增加，分别与野生型和mdx小鼠相比。Themdx：Flt-1+/−小鼠与themdx小鼠相比，肌肉组织学改善，纤维化、钙化和膜通透性降低。在功能上，与themdx小鼠相比，themdx：Flt-1+/−小鼠的肌肉血流量和力量产生增加。因此，与themdx：utrophin−/−小鼠相比，themdx：utrophin−/−：Flt-1+/−小鼠显示出改善的肌肉组织学和显著更高的存活率，themdx：utrophin−/−小鼠显示出比themdx小鼠更严重的肌肉表型。这些数据表明，增加DMD中的脉管系统可以改善与这种疾病相关的组织学和功能表型。
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,mdxmice, an animal model for DMD, were crossed withFlt-1gene 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-1gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show thatFlt-1+/−andmdx:Flt-1+/−adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type andmdxmice, respectively. Themdx:Flt-1+/−mice show improved muscle histology compared with themdxmice with decreased fibrosis, calcification and membrane permeability. Functionally, themdx:Flt-1+/−mice have an increase in muscle blood flow and force production, compared with themdxmice. Consequently, themdx:utrophin−/−:Flt-1+/−mice display improved muscle histology and significantly higher survival rates compared with themdx:utrophin−/−mice, which show more severe muscle phenotypes than themdxmice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease.
登录
查看更多内容
影响因子：
20.3
作者：
Kearney, JB;Ambler, CA;Bautch, VL
通讯作者：
Bautch, VL
影响因子：
12.7
作者：
CULLEN, MJ;JAROS, E
通讯作者：
JAROS, E
DOI：
10.1111/j.1365-2990.1988.tb00866.x
发表时间：
1988-01-01
影响因子：
5
作者：
COULTON, GR;MORGAN, JE;SLOPER, JC
通讯作者：
SLOPER, JC
影响因子：
56.9
作者：
MENDELL, JR;ENGEL, WK;DERRER, EC
通讯作者：
DERRER, EC
在肌营养不良蛋白缺乏的骨骼肌中，剪切应力下肌内小动脉的血管舒张功能会因 nNOS 表达减少而受损。
影响因子：
--
作者：
K. Sato;T. Yokota;S. Ichioka;M. Shibata;S. Takeda
通讯作者：
S. Takeda