Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells.
Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells.
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DOI：
10.1161/circresaha.113.301921
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发表时间：
2013-09-27
影响因子：
20.1
通讯作者：
Chen SY
中科院分区：
文献类型：
--
作者：
Xie WB;Li Z;Shi N;Guo X;Tang J;Ju W;Han J;Liu T;Bottinger EP;Chai Y;Jose PA;Chen SY
神经嵴细胞分化为血管平滑肌细胞（VSMC）是心血管发育的关键，但其机制尚不清楚。TGF-β在VSMC从NCC分化中的功能是有争议的。因此，我们确定了TGF-β下游信号中间体Smad 2在NCC向VSMC分化中的作用和机制。我们利用Cre/loxP系统建立了NCC组织特异性Smad 2基因敲除小鼠模型，发现Smad 2基因敲除导致NCC在胚胎发育过程中向主动脉弓动脉VSMCs的分化缺陷，并导致NCC来源的成人颈动脉VSMCs的血管壁异常。异常包括动脉中膜中缺少一层VSMC，弹性膜扭曲且变薄，导致与野生型血管相比血管壁变薄。在机制上，Smad 2与MRTFB相互作用以调节VSMC标记基因的表达。TGF-β诱导的MRTFB核转位需要Smad 2的参与，而MRTFB可增强Smad 2与VSMC标志启动子的结合。此外，我们发现Smad 2，而不是Smad 3，是一个祖细胞特异性转录因子，介导TGF-β诱导的VSMC从NCC分化。Smad 2似乎也参与确定NCC和中胚层来源的VSMCs之间的生理差异。Smad 2是调节祖细胞特异性VSMC发育以及NCC和中胚层来源的VSMC之间生理差异的重要因子。
Vascular smooth muscle cell (VSMC) differentiation from neural crest cells (NCCs) is critical for cardiovascular development, but the mechanisms remain largely unknown. TGF-β function in VSMC differentiation from NCCs is controversial. We therefore determined the role and the mechanism of a TGF-β downstream signaling intermediate Smad2 in NCC differentiation to VSMCs. By using Cre/loxP system, we generated NCC tissue-specific Smad2 knockout mouse model and found that Smad2 deletion resulted in defective NCC differentiation to VSMCs in aortic arch arteries during embryonic development and caused vessel wall abnormality in adult carotid arteries where the VSMCs are derived from NCCs. The abnormalities included missing one layer of VSMCs in the media of the arteries with distorted and thinner elastic lamina, leading to a thinner vessel wall as compared to the wild type vessel. Mechanistically, Smad2 interacted with MRTFB to regulate VSMC marker gene expression. Smad2 was required for TGF-β-induced MRTFB nuclear translocation whereas MRTFB enhanced Smad2 binding to VSMC marker promoter. Moreover, we found that Smad2, but not Smad3, was a progenitor-specific transcription factor mediating TGF-β-induced VSMC differentiation from NCCs. Smad2 appeared to be also involved in determining the physiological differences between NCC- and mesoderm-derived VSMCs. Smad2 is an important factor in regulating progenitor-specific VSMC development and physiological differences between NCC- and mesoderm-derived VSMCs.