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http://purl.uniprot.org/citations/23387849http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23387849http://www.w3.org/2000/01/rdf-schema#comment"

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-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."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.org/dc/terms/identifier"doi:10.1111/jth.12159"xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Zhou J."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Chien S."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Lim S.H."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Lee P.L."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Chiu J.J."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Lee C.I."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Lin T.E."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/author"Wei S.Y."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/date"2013"xsd:gYear
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/name"J Thromb Haemost"xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/pages"741-755"xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/title"BMP receptor-integrin interaction mediates responses of vascular endothelial Smad1/5 and proliferation to disturbed flow."xsd:string
http://purl.uniprot.org/citations/23387849http://purl.uniprot.org/core/volume"11"xsd:string
http://purl.uniprot.org/citations/23387849http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/23387849
http://purl.uniprot.org/citations/23387849http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/23387849
http://purl.uniprot.org/uniprot/#_Q15797-mappedCitation-23387849http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23387849
http://purl.uniprot.org/uniprot/#_Q6I9T1-mappedCitation-23387849http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23387849
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http://purl.uniprot.org/uniprot/#_Q99717-mappedCitation-23387849http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23387849
http://purl.uniprot.org/uniprot/Q68DB7http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/23387849
http://purl.uniprot.org/uniprot/Q99717http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/23387849
http://purl.uniprot.org/uniprot/Q15797http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/23387849
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