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10.1016/j.cellsig.2016.02.011

http://scihub22266oqcxt.onion/10.1016/j.cellsig.2016.02.011
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suck abstract from ncbi


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pmid26912210
      Cell+Signal 2016 ; 28 (5 ): 498-505
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  • A crosstalk between TGF-?/Smad3 and Wnt/?-catenin pathways promotes vascular smooth muscle cell proliferation #MMPMID26912210
  • DiRenzo DM ; Chaudhary MA ; Shi X ; Franco SR ; Zent J ; Wang K ; Guo LW ; Kent KC
  • Cell Signal 2016[May]; 28 (5 ): 498-505 PMID26912210 show ga
  • RATIONALE: 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-?/Smad3 promotes SMC proliferation and intimal hyperplasia. Furthermore in cultured SMCs, elevated TGF-?/Smad3 increases the expression of several Wnt genes. Here we investigate a crosstalk between TGF-?/Smad3 and Wnt/?-catenin signaling and its role in SMC proliferation. METHODS AND RESULTS: To mimic TGF-?/Smad3 up-regulation in vivo, rat aortic SMCs were treated with Smad3-expressing adenovirus (AdSmad3) or AdGFP control followed by stimulation with TGF-?1 (or solvent). AdSmad3/TGF-? treatment up-regulated Wnt2b, Wnt4, Wnt5a, Wnt9a, and Wnt11 (confirmed by qRT-PCR and ELISA), and also increased ?-catenin protein as detected by Western blotting. Blocking Wnt signaling using a Frizzled receptor inhibitor (Niclosamide) abolished TGF-?/Smad3-induced ?-catenin stabilization. Increasing ?-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 ?-catenin and stimulated SMC proliferation as well. In addition, increased ?-catenin was found in the neointima of injured rat carotid artery where TGF-? and Smad3 are known to be up-regulated. CONCLUSIONS: These results suggest a novel mechanism whereby elevated TGF-?/Smad3 stimulates the secretion of canonical Wnts which in turn enhances SMC proliferation through ?-catenin stabilization. This crosstalk between TGF-?/Smad3 and Wnt/?-catenin canonical pathways provides new insights into the pathophysiology of vascular SMCs linked to intimal hyperplasia.
  • |*Wnt Signaling Pathway [MESH]
  • |Animals [MESH]
  • |Aorta/cytology [MESH]
  • |Carotid Artery Diseases/metabolism/pathology [MESH]
  • |Cell Proliferation [MESH]
  • |Male [MESH]
  • |Muscle, Smooth, Vascular/cytology/*metabolism [MESH]
  • |Myocytes, Smooth Muscle/cytology/*metabolism [MESH]
  • |Neointima/metabolism [MESH]
  • |Rats, Sprague-Dawley [MESH]
  • |Smad3 Protein/*metabolism [MESH]
  • |Transforming Growth Factor beta/*metabolism [MESH]
  • |Wnt Proteins/genetics/metabolism [MESH]


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