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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.