國家衛生研究院 NHRI:Item 3990099045/7051
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    题名: BMP receptor-integrin interaction mediates responses of vascular endothelial smad1/5 and proliferation to disturbed flow
    作者: Zhou, J;Lee, PL;Lee, CI;Wei, SY;Lim, SH;Lin, TE;Chien, S;Chiu, JJ
    贡献者: Institute of Cellular and Systems Medicine
    摘要: 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 intraarterially 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: Intraarterial administration of Lenti-shSmad5 inhibited bromodeoxyuridine uptake of ECs at post-stenotic sites, where disturbed flow with OSS occurs. OSS induced sustained BMPRIB-alpha(v) beta(3) 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: OSS 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.
    日期: 2013-04
    關聯: Journal of Thrombosis and Haemostasis. 2013 Apr;11(4):741-755.
    Link to: http://dx.doi.org/10.1111/jth.12159
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1538-7933&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000317615500023
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84876182757
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