title: Mechanisms of TGF-β-induced differentiation in human vascular smooth muscle cells.
abstract: BACKGROUND
  Transforming growth factor-β (TGF-β) plays an important role in vascular homeostasis through effects on vascular smooth muscle cells (SMC). Fine-tuning of TGF-β signaling occurs at the level of ALK receptors or Smads, and is regulated with cell type specificity.
  
  
  METHODS
  Our goal was to understand TGF-β signaling in regulating SMC differentiation marker expression in human SMC. Activation of Smads was characterized, and loss- and gain-of-function reagents used to define ALK pathways. In addition, Smad-independent mechanisms were determined.
  
  
  RESULTS
  TGF-β type I receptors, ALK1 and ALK5, are expressed in human SMC, and TGF-β1 phosphorylates Smad1/5/8 and Smad2/3 in a time- and dosage-dependent pattern. ALK5 activity, not bone morphogenetic protein type I receptors, is required for Smad phosphorylation. Endoglin, a TGF-β type III receptor, is a TGF-β1 target in SMC, yet endoglin does not modify TGF-β1 responsiveness. ALK5, not ALK1, is required for TGF-β1-induction of SMC differentiation markers, and ALK5 signals through an ALK5/Smad3- and MAP kinase-dependent pathway.
  
  
  CONCLUSIONS
  The definition of the specific signaling downstream of TGF-β regulating SMC differentiation markers will contribute to a better understanding of vascular disorders involving changes in SMC phenotype.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Tang
authors.forename: Xuehui
authors.initials: X
authors.lastname: Yang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Friesel
authors.forename: Calvin P H
authors.initials: CP
authors.lastname: Vary
authors.forename: Lucy
authors.initials: L
authors.lastname: Liaw
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000166:cytology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000071063:Endoglin; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human