title: BMP receptor-integrin interaction mediates responses of vascular endothelial Smad1/5 and proliferation to disturbed flow.
abstract: BACKGROUND
  Vascular endothelial cells (ECs) are constantly exposed to blood flow-induced shear stress. Our previous study demonstrated that disturbed flow with low and oscillatory shear stress (OSS) induces bone morphogenetic protein receptor (BMPR)-specific Smad1/5 activation in ECs, but the underlying mechanisms and the in vivo functional role of Smad1/5 remain unclear.
  
  
  OBJECTIVE
  Here we elucidated the molecular mechanisms by which OSS activates EC Smad1/5 and its in vivo functional role.
  
  
  METHODS
  Lentiviral Smad5-specific short hairpin RNA (Lenti-shSmad5) was constructed and intra-arterially injected into the lumen of stenosed abdominal aorta in bromodeoxyuridine-infused rats. Co-immunoprecipitation and in situ proximity ligation assays were performed on ECs exposed to OSS (0.5 ± 4 dynes/cm(2) ) in a parallel-plate flow chamber to investigate BMPR-integrin interactions and their regulatory role in OSS-activation of EC Smad1/5.
  
  
  RESULTS
  Intra-arterial administration of Lenti-shSmad5 inhibited bromodeoxyuridine uptake of ECs at post-stenotic sites, where disturbed flow with OSS occurs. OSS induced sustained BMPRIB-αv β3 integrin association in ECs, which was mediated by the intracytoplasmic kinase domain of BMPRII and subsequently activated the Shc/focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) cascade, leading to Smad1/5 activation. This OSS-activation of Smad1/5 induced its association with and activation of runt-related transcription factor-2 (Runx2), leading to activations of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K), a pathway critical for EC proliferation in response to OSS.
  
  
  CONCLUSIONS
  Oscillatory shear stress induces synergistic interactions between specific BMPRs and integrin to activate Smad1/5 through the Shc/FAK/ERK pathway, which leads to the activation of the Runx2/mTOR/p70S6K pathway to promote EC proliferation.
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: J
authors: J
authors: Zhou
authors: P-L
authors: PL
authors: Lee
authors: C-I
authors: CI
authors: Lee
authors: S-Y
authors: SY
authors: Wei
authors: S H
authors: SH
authors: Lim
authors: T-E
authors: TE
authors: Lin
authors: S
authors: S
authors: Chien
authors: J-J
authors: JJ
authors: Chiu
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008297:Male; D051381:Rats; D051898:Smad1 Protein / Q000502:physiology*; D051902:Smad5 Protein / Q000502:physiology*
chemical_list: D016023:Integrins; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D052004:Bone Morphogenetic Protein Receptors