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

ABSTRACT: OBJECTIVE:Smooth muscle cells (SMCs) contribute to neointima formation after vascular injury. Although ?-catenin expression is induced after injury, whether its function is essential in SMCs for neointimal growth is unknown. Moreover, although inhibitors of ?-catenin have been developed, their effects on SMC growth have not been tested. We assessed the requirement for SMC ?-catenin in short-term vascular homeostasis and in response to arterial injury and investigated the effects of ?-catenin inhibitors on vascular SMC growth. APPROACH AND RESULTS:We used an inducible, conditional genetic deletion of ?-catenin in SMCs of adult mice. Uninjured arteries from adult mice lacking SMC ?-catenin were indistinguishable from controls in terms of structure and SMC marker gene expression. After carotid artery ligation, however, vessels from mice lacking SMC ?-catenin developed smaller neointimas, with lower neointimal cell proliferation and increased apoptosis. SMCs lacking ?-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, ?-catenin inhibitors PKF118-310 and ICG-001 limited growth of mouse and human vascular SMCs in a dose-dependent manner. CONCLUSIONS:SMC ?-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. Pharmacological ?-catenin inhibitors hinder growth of human vascular SMCs. Thus, inhibiting ?-catenin has potential as a therapy to limit SMC accumulation and vascular obstruction.

SUBMITTER: Riascos-Bernal DF

PROVIDER: S-EPMC5408313 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Riascos-Bernal Dario F DF Chinnasamy Prameladevi P Gross Jordana N JN Almonte Vanessa V Egaña-Gorroño Lander L Parikh Dippal D Jayakumar Smitha S Guo Liang L Sibinga Nicholas E S NES

Arteriosclerosis, thrombosis, and vascular biology 20170316 5

<h4>Objective</h4>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-cat ...[more]

PMID: 28302627

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Project description:Background3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.Methodology/principal findingsDIM dose-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptor? (PDGF-R?) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3?, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.ConclusionThese results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-R? and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis.

Dataset Information

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

Publications

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

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