R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Slater, S. D.; Koutsouki, Evgenia; Jackson, Christopher L.; Bush, Raymond C.; Angelini, Gianni; Newby, Andrew C.; George, Sarah J.

doi:10.1161/01.atv.0000130464.24599.e0

Cited by 71 publications

(69 citation statements)

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“…Firstly, balloon injury of the rat carotid artery, which induces VSMC proliferation, also results in upregulation of ␤-catenin protein levels. 5,7,18 Additionally, we have demonstrated that growth factor stimulation of VSMC proliferation in vitro augmented active ␤-catenin levels and association of ␤-catenin with LEF-1. 4 Moreover, we have identified that growth factor stimulation results in modulation of cyclin D1 and p21 expression in VSMCs in vitro, via induction of endogenous ␤-catenin/TCF signaling.…”

Section: Discussionmentioning

confidence: 84%

“…We previously showed that activation of ␤-catenin signaling, as a result of dismantling of N-cadherin-mediated cell-cell contacts, induced VSMC proliferation in vitro, via modulation of the expression of the cell cycle genes cyclin D1 and p21. 4,6 Moreover, dismantling of cadherin:␤-catenin complexes occurred in vivo during medial VSMC proliferation in balloon-injured rat carotid arteries, and was associated with increased expression of cyclin D1, 5 indicating ␤-catenin signaling also regulates VSMC proliferation in vivo. This is corroborated by the detection of elevated levels of ␤-catenin after balloon injury in rat carotid arteries.…”

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confidence: 98%

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Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

Tsaousi

Williams

Lyon

et al. 2011

Circulation Research

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144

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Rationale: Vascular smooth muscle cell (VSMC) proliferation causes intimal thickening in atherosclerosis andrestenosis. Previously, we demonstrated that Wnt/␤-catenin signaling upregulates VSMC proliferation in vitro.Objective: We examined this pathway in vivo and investigated the involvement of specific Wnt proteins in VSMC proliferation. Methods and Results:Left carotid arteries of TOPgal (␤-catenin signaling reporter) transgenic mice were ligated to induce intimal thickening. ␤-Catenin signaling was induced in the media and intima at 3 and 28 days after ligation, respectively, and was associated with VSMC proliferation and cyclin D1 expression. In vitro, a Wnt agonist promoted mouse VSMC proliferation, whereas Wnt inhibitory factor (WIF)-1 retarded platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation. Microarray analysis and quantitative PCR detected a significant induction of Wnt2 and Wnt4 mRNA in PDGF-BB-treated (proliferating) VSMCs compared to quiescent VSMCs. Western blotting revealed this increase was only translated into protein for Wnt4. Specific silencing RNA knockdown of Wnt4, but not Wnt2, significantly reduced VSMC proliferation. Recombinant Wnt4, but not Wnt2, significantly increased VSMC proliferation by Ϸ2-fold and silencing RNA knockdown revealed this is via Frizzled 1. Immunohistochemistry showed that increased Wnt4 protein correlated with VSMC proliferation and cyclin D1 expression (P<0.05 and P<0.001, respectively) during intimal thickening after rat carotid artery injury. Importantly, we also showed that intimal thickening and VSMC proliferation after carotid artery ligation was significantly retarded in Wnt4 ؉/؊ compared to Wnt4 ؉/؉ mice. nappropriate vascular smooth muscle cell (VSMC) activation plays a key role in pathologies that involve intimal thickening, such as atherosclerosis and restenosis after angioplasty and vein grafting. 1,2 Intimal thickening occurs as a result of augmented VSMC proliferation, in addition to increased VSMC migration, extracellular matrix synthesis and phenotypic change. 3 Recently, we and others have proposed that the Wnt/␤-catenin pathway is a novel regulator of VSMC proliferation and thereby intimal thickening. 4 -10 The Wnt family (comprised of 19 secreted, lipid-modified glycoproteins) plays a crucial role not only in the regulation of embryogenesis and development, but also in cell proliferation, differentiation, polarity, migration, and invasion (see review 11 ). Wnt proteins activate downstream signaling pathways (in a paracrine and autocrine manner) after binding to cell surface Frizzled (Fzd) receptors. 12 Abnormal Wnt signaling is associated with many human diseases, including cancer and degenerative diseases 11 ; however, the involvement of Wnt signaling in atherosclerosis and restenosis remains to be fully elucidated. ConclusionsAlthough Wnt signaling via ␤-catenin has a recognized role in controlling the proliferation of cells in human cancers, 13 its role in VSMCs has only recently been considered. We previously showed that ...

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 98%

Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

Tsaousi

Williams

Lyon

et al. 2011

Circulation Research

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144

123

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“…Statistical significance determined by 1-way ANOVA followed by a Newman-Keuls multiple-comparison test. cretion and ECM protein production, including fibronectin and versican (14,18,59,60,62,63). Collectively, these findings indicate a central role for ␤-catenin in many cellular responses that underpin smooth muscle remodeling in both the airways and the vasculature (30).…”

Section: Discussionmentioning

confidence: 94%

β-Catenin signaling is required for TGF-β₁-induced extracellular matrix production by airway smooth muscle cells

Baarsma

Menzen

Halayko

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway remodeling with altered extracellular matrix (ECM) deposition. Transforming growth factor-β1 (TGF-β1) is upregulated in asthma and COPD and contributes to tissue remodeling in the airways by driving ECM production by structural cells, including airway smooth muscle. In this study, we investigated the activation of β-catenin signaling and its contribution to ECM production by airway smooth muscle cells in response to TGF-β1. Stimulation of airway smooth muscle cells with TGF-β1 resulted in a time-dependent increase of total and nonphosphorylated β-catenin protein expression via induction of β-catenin mRNA and inhibition of GSK-3. In addition, the TGF-β1-induced β-catenin activated TCF/LEF-dependent gene transcription, as determined by the β-catenin sensitive TOP-flash luciferase reporter assay. Furthermore, TGF-β1 stimulation increased mRNA expression of collagen Iα1, fibronectin, versican, and PAI-1. Pharmacological inhibition of β-catenin by PKF115-584 or downregulation of β-catenin expression by specific small interfering RNA (siRNA) substantially inhibited TGF-β1-induced expression of the ECM genes. Fibronectin protein deposition by airway smooth muscle cells in response to TGF-β1 was also inhibited by PKF115-584 and β-catenin siRNA. Moreover, transfection of airway smooth muscle cells with a nondegradable β-catenin mutant (S33Y β-catenin) was sufficient for inducing fibronectin protein expression. Collectively, these findings indicate that β-catenin signaling is activated in response to TGF-β1 in airway smooth muscle cells, which is required and sufficient for the regulation of ECM protein production. Targeting β-catenin-dependent gene transcription may therefore hold promise as a therapeutic intervention in airway remodeling in both asthma and COPD.

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“…13 A link between b-catenin stabilization and smooth muscle cell proliferation has been demonstrated both in vitro and after balloon catheter injury. 7,10,43 Oxidized LDL has also been shown to stimulate smooth muscle cell migration in a mechanism that was dependent on b-catenin signaling. 44 A number of confirmed Wnt target genes, including versican, 19 fibronectin 45 and matrix metalloproteases, 46 are upregulated after vascular injury and appear to promote inflammation and atheroma formation.…”

Section: Discussionmentioning

confidence: 99%

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy

Luo

McManus

2012

Laboratory Investigation

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Evidence suggests a role for Wnt signaling in vascular wound repair and remodeling events. Despite this, very little is known about the effect of Wnt ligands on the structure and function of vascular cells. In this study, we treated vascular smooth muscle cells with 250 ng/ml of recombinant Wnt3a for 72 h and observed changes in the cell phenotype. Our data suggest Wnt3a completely alters the phenotype of vascular smooth muscle cells. The Wnt3a-treated cells appeared larger and had increased formation of stress fibers. These cells also had increased expression of the smooth muscle contractile proteins, calponin and smooth muscle a-actin, and contracted a collagen lattice faster than control cells. The Wnt3a-treated smooth muscle cells displayed increased extracellular matrix synthesis, as measured by collagen I and III mRNA expression, along with increased expression of MMP2 and MMP9, but decreased TIMP2 levels. The Wnt3a-induced change in cell phenotype was associated with increased expression of the gap junction protein connexin 43. Consistent with this, Wnt3a-treated smooth muscle cells displayed enhanced intercellular communication, as measured by the scrape-loading dye transfer technique. The canonical Wnt antagonist, dickkopf-related protein 1, completely reversed the contractile protein and connexin 43 expression seen in the Wnt3a-treated cells, suggesting these changes were dependent on canonical Wnt signaling. Collectively, this data suggest Wnt3a promotes a contractile and secretory phenotype in vascular smooth muscle cells that is associated with increased gap junction communication. Numerous studies have demonstrated that after arterial injury, vessel walls follow a response-to-injury pattern of wound healing leading to stenosis secondary to the neointimal accumulation of smooth muscle cells and extracellular matrix. 1-4 A number of soluble mediators released at the site of vascular injury act as molecular cues that guide smooth muscle cell responses during repair. 5,6 Growing evidence suggest a role for the Wnt family of secreted glycoproteins and their associated signaling pathways in regulating many of the processes involved in vascular wound repair and remodeling events. [7][8][9][10][11][12][13][14] However, the precise mechanisms and outcomes of Wnt signaling in such settings remain unclear. Moreover, the effect of specific Wnt family members on vascular cell phenotype remain undefined.The Wnt signaling pathway is best recognized for its role in the development of multi-cellular organisms, 15,16 and is critically involved in normal heart formation. 17 The Wnt family is comprised of 19 secreted glycoproteins that bind the Frizzled receptor and its co-receptor, lipoprotein receptorrelated proteins 5/6, to initiate an intracellular signaling cascade that controls the turnover of b-catenin. 18 In the absence of Wnt ligand, b-catenin is targeted for ubiquitinmediated degradation by the 26S proteasome. However, upon ligand stimulation, canonical Wnt signaling triggers a series of phosphorylation even...

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R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Cited by 71 publications

References 33 publications

Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

β-Catenin signaling is required for TGF-β₁-induced extracellular matrix production by airway smooth muscle cells

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

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R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Cited by 71 publications

References 33 publications

Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

Wnt4/β-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening

β-Catenin signaling is required for TGF-β1-induced extracellular matrix production by airway smooth muscle cells

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

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β-Catenin signaling is required for TGF-β₁-induced extracellular matrix production by airway smooth muscle cells