title: A crosstalk between TGF-β/Smad3 and Wnt/β-catenin pathways promotes vascular smooth muscle cell proliferation.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: DiRenzo
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Mirnal A
authors.initials: MA
authors.lastname: Chaudhary
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Xudong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Franco
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Joshua
authors.initials: J
authors.lastname: Zent
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Katie
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, U.S.A.|Department of Surgery, Wisconsin Institute for Medical Research, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, U.S.A.
authors.forename: K Craig
authors.initials: KC
authors.lastname: Kent
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Proliferation; TGF-β/Smad3; Vascular smooth muscle cells; Wnt/β-catenin