A crosstalk between TGF-β/Smad3 and Wnt/β-catenin pathways promotes vascular smooth muscle cell proliferation.
A crosstalk between TGF-β/Smad3 and Wnt/β-catenin pathways promotes vascular smooth muscle cell proliferation.
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DOI：
10.1016/j.cellsig.2016.02.011
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发表时间：
2016-05
影响因子：
4.8
通讯作者：
Kent KC
中科院分区：
文献类型：
--
作者：
DiRenzo DM;Chaudhary MA;Shi X;Franco SR;Zent J;Wang K;Guo LW;Kent KC
对动脉粥样硬化病变进行血管内介入治疗会引发过度的血管平滑肌细胞（SMC）增殖，导致内膜增生。我们的前期研究表明血管内损伤后，TGF-β/Smad 3升高促进SMC增殖和内膜增生。此外，在培养的SMC中，升高的TGF-β/Smad 3增加了几种Wnt基因的表达。我们研究了TGF-β/Smad 3和Wnt/β-catenin信号通路之间的相互作用及其在SMC增殖中的作用。为了模拟体内TGF-β/Smad 3上调，用表达Smad 3的腺病毒（AdSmad 3）或AdGFP对照处理大鼠主动脉SMC，然后用TGF-β1（或溶剂）刺激。AdSmad 3/TGF-β处理上调Wnt 2b、Wnt 4、Wnt 5a、Wnt 9a和Wnt 11（通过qRT-PCR和ELISA证实），并且通过Western印迹检测还增加β-catenin蛋白。使用卷曲受体抑制剂（氯硝柳胺）阻断Wnt信号传导消除了TGF-β/Smad 3诱导的β-连环蛋白稳定。通过降解抑制（使用SKL 2001）或通过腺病毒表达增加β-连环蛋白增强SMC增殖。此外，应用重组Wnt 2b、Wnt 4、Wnt 5a或Wnt 9a，但不应用Wnt 11，稳定β-连环蛋白并刺激SMC增殖。此外，在损伤的大鼠颈动脉的新生内膜中发现增加的β-连环蛋白，其中已知TGF-β和Smad 3上调。这些结果提示了一种新的机制，即升高的TGF-β/Smad 3刺激典型Wnt的分泌，这反过来又通过β-连环蛋白稳定化增强SMC增殖。TGF-β/Smad 3和Wnt/β-catenin经典途径之间的这种相互作用为与内膜增生相关的血管SMC的病理生理学提供了新的见解。
Endovascular interventions performed for atherosclerotic lesions trigger excessive vascular smooth muscle cell (SMC) proliferation leading to intimal hyperplasia. Our previous studies show that following endovascular injury, elevated TGF-β/Smad3 promotes SMC proliferation and intimal hyperplasia. Furthermore in cultured SMCs, elevated TGF-β/Smad3 increases the expression of several Wnt genes. Here we investigate a crosstalk between TGF-β/Smad3 and Wnt/β-catenin signaling and its role in SMC proliferation. To mimic TGF-β/Smad3 up-regulation in vivo, rat aortic SMCs were treated with Smad3-expressing adenovirus (AdSmad3) or AdGFP control followed by stimulation with TGF-β1 (or solvent). AdSmad3/TGF-β treatment up-regulated Wnt2b, Wnt4, Wnt5a, Wnt9a, and Wnt11 (confirmed by qRT-PCR and ELISA), and also increased β-catenin protein as detected by Western blotting. Blocking Wnt signaling using a Frizzled receptor inhibitor (Niclosamide) abolished TGF-β/Smad3-induced β-catenin stabilization. Increasing β-catenin through degradation inhibition (using SKL2001) or by adenoviral expression enhanced SMC proliferation. Furthermore, application of recombinant Wnt2b, Wnt4, Wnt5a, or Wnt9a, but not Wnt11, stabilized β-catenin and stimulated SMC proliferation as well. In addition, increased β-catenin was found in the neointima of injured rat carotid artery where TGF-β and Smad3 are known to be up-regulated. These results suggest a novel mechanism whereby elevated TGF-β/Smad3 stimulates the secretion of canonical Wnts which in turn enhances SMC proliferation through β-catenin stabilization. This crosstalk between TGF-β/Smad3 and Wnt/β-catenin canonical pathways provides new insights into the pathophysiology of vascular SMCs linked to intimal hyperplasia.