title: TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections.
abstract: OBJECTIVE
  Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs.
  
  
  RESULTS
  Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins.
  
  
  CONCLUSIONS
  These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD.
authors.affiliation: Department of Internal Medicine and Cardiothoracic and Vascular Surgery, University of Texas Medical School at Houston, MSB 6.100, 6431, Fannin St, Houston, TX 77030, USA.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Inamoto
authors.forename: Callie S
authors.initials: CS
authors.lastname: Kwartler
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Lafont
authors.forename: Yao Yun
authors.initials: YY
authors.lastname: Liang
authors.forename: Van Tran
authors.initials: VT
authors.lastname: Fadulu
authors.forename: Senthil
authors.initials: S
authors.lastname: Duraisamy
authors.forename: Marcia
authors.initials: M
authors.lastname: Willing
authors.forename: Anthony
authors.initials: A
authors.lastname: Estrera
authors.forename: Hazim
authors.initials: H
authors.lastname: Safi
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hannibal
authors.forename: John
authors.initials: J
authors.lastname: Carey
authors.forename: John
authors.initials: J
authors.lastname: Wiktorowicz
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Hariyadarshi
authors.initials: H
authors.lastname: Pannu
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000199:Actins / Q000378:metabolism; D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000096985:Calponins