TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A
TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A
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DOI：
10.1093/jb/mvr121
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发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Watabe, Tetsuro
中科院分区：
文献类型：
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作者：
Mihira, Hajime;Suzuki, Hiroshi I.;Watabe, Tetsuro
内皮-间质转化（EndMT）在多种生理和病理过程中起着重要作用。虽然由转化生长因子（TGF）-β介导的信号已经与EndMT有关，但其潜在的分子机制仍有待充分阐明。在这里，我们研究了TGF-β信号对小鼠胰腺微血管内皮细胞（MS-1）EndMT的影响。通过加入TGF-β 2，MS-1细胞经历了间充质转化，其特征在于肌动蛋白应力纤维的重组和各种间充质标志物如α-平滑肌肌动蛋白（α-SMA）通过Rho信号的激活而增加的表达。尽管通过TGF-β诱导的非Smad信号激活Rho信号与上皮-间充质转化（EMT）有关，但我们发现，鸟嘌呤核苷酸交换因子Arhgef 5由Smad信号诱导，并有助于TGF-β 2诱导的MS-1细胞中的α-SMA表达。我们还发现，TGF-β 2诱导心肌相关转录因子-A（MRTF-A）的表达在一个Smad依赖的方式和其在MS-1细胞核中的积累，MRTF-A是必需的和足够的TGF-β 2诱导的α-SMA的表达。这些结果表明，TGF-β 2激活Smad信号对Rho信号和MRTF-A的激活具有双重作用，导致MS-1内皮细胞的间质转化。
Endothelial-mesenchymal transition (EndMT) plays important roles in various physiological and pathological processes. While signals mediated by transforming growth factor (TGF)-beta have been implicated in EndMT, the molecular mechanisms underlying it remain to be fully elucidated. Here, we examined the effects of TGF-beta signals on the EndMT of mouse pancreatic microvascular endothelial cells (MS-1). By addition of TGF-beta 2, MS-1 cells underwent mesenchymal transition characterized by re-organization of actin stress fibre and increased expression of various mesenchymal markers such as alpha-smooth muscle actin (alpha-SMA) through activation of Rho signals. Whereas activation of Rho signals via TGF-beta-induced non-Smad signals has been implicated in epithelial-mesenchymal transition (EMT), we found that Arhgef5, a guanine nucleotide exchange factor, is induced by Smad signals and contributes to the TGF-beta 2-induced alpha-SMA expression in MS-1 cells. We also found that TGF-beta 2 induces the expression of myocardin-related transcription factor-A (MRTF-A) in a Smad-dependent fashion and its nuclear accumulation in MS-1 cells and that MRTF-A is required and sufficient for TGF-beta 2-induced alpha-SMA expression. These results indicate that activation of Smad signals by TGF-beta 2 have dual effects on the activation of Rho signals and MRTF-A leading to the mesenchymal transition of MS-1 endothelial cells.