A crosstalk between TGF-?/Smad3 and Wnt/?-catenin pathways promotes vascular smooth muscle cell proliferation.

ABSTRACT: 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.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.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.

SUBMITTER: DiRenzo DM 

PROVIDER: S-EPMC4788971 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature