title: Inhibition of Smooth Muscle β-Catenin Hinders Neointima Formation After Vascular Injury.
abstract: 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.
  
  
  
  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 ofMmp2,Mmp9,Sphk1, andS1pr1(genes that promote neointima formation), higher levels ofJag1andGja1(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.
  
  
  
  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. Pharmacological 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.
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Dario F
authors.initials: DF
authors.lastname: Riascos-Bernal
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Prameladevi
authors.initials: P
authors.lastname: Chinnasamy
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Jordana N
authors.initials: JN
authors.lastname: Gross
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almonte
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Lander
authors.initials: L
authors.lastname: Egaña-Gorroño
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Dippal
authors.initials: D
authors.lastname: Parikh
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Smitha
authors.initials: S
authors.lastname: Jayakumar
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.).
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY (D.F.R.-B., P.C., J.N.G., V.A., L.E.-G., D.P., S.J., N.E.S.S.); and CVPath Institute, Gaithersburg, MD (L.G.). nicholas.sibinga@einstein.yu.edu.
authors.forename: Nicholas E S
authors.initials: NES
authors.lastname: Sibinga
mesh_terms: D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D066253:Vascular Remodeling; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C495267:CTNNB1 protein, mouse; C492448:ICG 001; C548732:PKF118-310; D011744:Pyrimidinones; D014227:Triazines; D051176:beta Catenin
keywords: beta-catenin; beta-catenin inhibitors; myocytes, smooth muscle; neointima; vascular injury