title: Transglutaminase 2 promotes PDGF-mediated activation of PDGFR/Akt1 and β-catenin signaling in vascular smooth muscle cells and supports neointima formation.
abstract: BACKGROUND
  Phenotypic switch of vascular smooth muscle cells (VSMCs) accompanies neointima formation and associates with vascular diseases. Platelet-derived growth factor (PDGF)-induced activation of PDGFR/Akt1 and β-catenin signaling pathways in VSMCs has been implicated in vessel occlusion. Transglutaminase 2 (TG2) regulates these pathways and its levels are increased in the neointima.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the role of TG2 in PDGF/β-catenin signaling cross-talk and assess its contribution to neointima.
  
  
  METHODS
  Aortic VSMCs from wild-type and TG2 knockout mice were tested in vitro for levels of VSMC markers, proliferation, migration and PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways. Neointima in these mice was studied ex vivo in coronary vessels using a heart slice model and in vivo using a carotid artery ligation model.
  
  
  RESULTS
  Genetic deletion of TG2 attenuated the PDGF-induced phenotypic switch of aortic VSMCs, reduced their proliferation and migration rates, and inhibited PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways in both ex vivo and in vivo neointima models. Importantly, genetic deletion of TG2 also markedly attenuated vessel occlusion.
  
  
  CONCLUSIONS
  TG2 promotes neointima formation by mediating the PDGF-induced activation of the PDGFR/Akt1 and β-catenin pathways in VSMCs. This study identifies TG2 as a potential therapeutic target for blocking neointima in blood vessels.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Md., USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Nurminskaya
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Beazley
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Smith
authors.forename: Alexey M
authors.initials: AM
authors.lastname: Belkin
mesh_terms: D000818:Animals; D000077214:Becaplermin; D016893:Carotid Stenosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023921:Coronary Stenosis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D020574:Proto-Oncogene Proteins c-sis; D051176:beta Catenin; D000077214:Becaplermin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D017479:Receptors, Platelet-Derived Growth Factor; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins