PMID- 23387849
OWN - NLM
STAT- MEDLINE
DCOM- 20130930
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 11
IP  - 4
DP  - 2013 Apr
TI  - BMP receptor-integrin interaction mediates responses of vascular endothelial 
      Smad1/5 and proliferation to disturbed flow.
PG  - 741-55
LID - 10.1111/jth.12159 [doi]
AB  - 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. OBJECTIVES: 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-alphav beta3 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.
CI  - (c) 2013 International Society on Thrombosis and Haemostasis.
FAU - Zhou, J
AU  - Zhou J
AD  - Institute of Cellular and System Medicine, National Health Research Institutes, 
      Miaoli, Taiwan.
FAU - Lee, P-L
AU  - Lee PL
FAU - Lee, C-I
AU  - Lee CI
FAU - Wei, S-Y
AU  - Wei SY
FAU - Lim, S H
AU  - Lim SH
FAU - Lin, T-E
AU  - Lin TE
FAU - Chien, S
AU  - Chien S
FAU - Chiu, J-J
AU  - Chiu JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Integrins)
RN  - 0 (SMAD1 protein, human)
RN  - 0 (SMAD5 protein, human)
RN  - 0 (Smad1 Protein)
RN  - 0 (Smad5 Protein)
RN  - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors)
SB  - IM
MH  - Animals
MH  - Bone Morphogenetic Protein Receptors/*metabolism
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Endothelium, Vascular/cytology/*metabolism
MH  - Humans
MH  - Integrins/*metabolism
MH  - Male
MH  - Rats
MH  - Smad1 Protein/*physiology
MH  - Smad5 Protein/*physiology
EDAT- 2013/02/08 06:00
MHDA- 2013/10/01 06:00
CRDT- 2013/02/08 06:00
PHST- 2012/08/01 00:00 [received]
PHST- 2013/01/25 00:00 [accepted]
PHST- 2013/02/08 06:00 [entrez]
PHST- 2013/02/08 06:00 [pubmed]
PHST- 2013/10/01 06:00 [medline]
AID - S1538-7836(22)13719-0 [pii]
AID - 10.1111/jth.12159 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2013 Apr;11(4):741-55. doi: 10.1111/jth.12159.