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

DiRenzo, Daniel; Chaudhary, Mirnal; Shi, Xudong; Franco, Sarah; Zent, Joshua; Wang, Katie; Guo, Lian‐Wang; Kent, K. Craig

doi:10.1016/j.cellsig.2016.02.011

Cited by 89 publications

(74 citation statements)

References 43 publications

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“…These studies show that SMC β-catenin is dispensable for the maintenance of uninjured adult vessels, but is required for neointimal formation after vascular injury. Moreover, β-catenin is required for expression of a set of genes reported to promote SMC invasion and neointimal growth, including matrix metallopeptidase 2 (Mmp2), and is necessary for SMC invasion in vitro ; this complements the pro-proliferative and pro-survival roles of SMC β-catenin previously reported 6–9, 16, 18, 21 . Finally, we found that inhibitors of β-catenin effectively reduced growth of mouse and human vascular SMCs in culture.…”

Section: Introductionmentioning

confidence: 66%

“…These studies show that 1) treatment of vascular SMCs in culture with recombinant Wnt2b, Wnt4, Wnt5a, or Wnt9a, but not Wnt11, increases β-catenin protein levels and cell proliferation 16 ; 2) treatment with recombinant Wnt2 increases Wisp1 mRNA levels and induces SMC migration 11 ; 3) balloon injury of carotid arteries in diabetic rats results in neointimal hyperplasia associated with increased Wnt4, Dvl-1, β-catenin, and cyclin D1 expression, and reduced p21 levels, a phenotype suppressed by up-regulation of microRNA-24 17 ; 4) aortas from rats fed a high-fat diet have increased numbers of SMCs and lipid droplets, associated with higher mRNA levels for Wnt3a, β-catenin, Tcf-4, and cyclin D1, suggesting a role for Wnt/β-catenin signaling in hyperlipidemia-induced SMC proliferation 18 ; and 5) in a model of Angiotensin II-induced arterial hypertension, complement C1q activates β-catenin signaling, which is required for vascular SMC proliferation 19 .…”

Section: Introductionmentioning

confidence: 74%

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Inhibition of Smooth Muscle β-Catenin Hinders Neointima Formation After Vascular Injury

Riascos-Bernal

Chinnasamy

Gross

et al. 2017

ATVB

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Objective Smooth muscle cells (SMCs) contribute to neointima formation after vascular injury. Although β-catenin expression is induced after injury, whether its function is essential in SMCs for neointimal growth is unknown. Moreover, although inhibitors of β-catenin have been developed, their effects on SMC growth have not been tested. We assessed the requirement for SMC β-catenin in short-term vascular homeostasis and in response to arterial injury, and investigated the effects of β-catenin inhibitors on vascular SMC growth. Approach and Results We used an inducible, conditional genetic deletion of β-catenin in SMCs of adult mice. Uninjured arteries from adult mice lacking SMC β-catenin were indistinguishable from controls in terms of structure and SMC marker gene expression. After carotid artery ligation, however, vessels from mice lacking SMC β-catenin developed smaller neointimas, with lower neointimal cell proliferation and increased apoptosis. SMCs lacking β-catenin showed decreased mRNA expression of Mmp2, Mmp9, Sphk1 and S1pr1 (genes that promote neointima formation), higher levels of Jag1 and Gja1 (genes that inhibit neointima formation), decreased Mmp2 protein expression and secretion, and reduced cell invasion in vitro. Moreover, β-catenin inhibitors PKF118-310 and ICG-001 limited growth of mouse and human vascular SMCs in a dose-dependent manner. Conclusions SMC β-catenin is dispensable for maintenance of the structure and state of differentiation of uninjured adult arteries, but is required for neointima formation after vascular injury. Pharmacologic β-catenin inhibitors hinder growth of human vascular SMCs. Thus inhibiting β-catenin has potential as a therapy to limit SMC accumulation and vascular obstruction.

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Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 74%

Inhibition of Smooth Muscle β-Catenin Hinders Neointima Formation After Vascular Injury

Riascos-Bernal

Chinnasamy

Gross

et al. 2017

ATVB

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“…Wnt7a and Wnt9a were recently shown to stimulate β-catenin signaling (83,84). The two small-molecular Wnt inhibitors XAV939 and LGK974 suppressed Wnt/β-catenin signaling, significantly extended life span, ameliorated cystic phenotypes, and improved renal functions in our mouse model of Pkd2-associated ADPKD ( Figure 6 and Supplemental Figure 9).…”

Section: +mentioning

confidence: 93%

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

Li¹,

Xu²,

Fan³

et al. 2018

JCI Insight

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“…Previous studies have identified TGF β as a critical molecular mediator and SMCs as the major cellular effectors in this repairing process (Bobik ; DiRenzo et al. ). To evaluate the effect of SMC‐specific TGF β signaling on regulating NIH and wall remodeling, we deleted SMC TGF β type I receptors (i.e., Tgfbr1 iko ) and characterized the phenotype of Tgfbr1 iko FAs following endothelial denudation and intramural dilation.…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries

et al. 2016

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Neointimal hyperplasia (NIH) and inward wall remodeling cause arterial restenosis and failure of bypass vein grafts. Previous studies from our group suggest that transforming growth factor (TGF) β promotes these pathologies via regulating cell kinetics at the early stage and matrix metabolism at the late stage. Although these temporal TGF β effects may result from its signaling in different cell groups, the responsible cell type has not been identified. In the current study, we evaluated the effect of smooth muscle cell (SMC)‐specific TGF β signaling through its type I receptor TGFBR1 on NIH and wall remodeling of the injured femoral arteries (FAs). An inducible Cre/loxP system was employed to delete SMC Tgfbr1 (Tgfbr1 iko). Mice not carrying the Cre allele (Tgfbr1 f/f) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1 iko attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1 f/f controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1 f/f FAs, however, Tgfbr1 iko FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1 iko FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1 f/f FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1 iko FAs than in that of Tgfbr1 f/f controls. Our results suggest that disruption of SMC Tgfbr1 inhibits arterial NIH in the short term, but the overall vascular phenotype may not favor long‐term performance of the injured arteries.

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

Cited by 89 publications

References 43 publications

Inhibition of Smooth Muscle β-Catenin Hinders Neointima Formation After Vascular Injury

Inhibition of Smooth Muscle β-Catenin Hinders Neointima Formation After Vascular Injury

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries

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