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BMP receptor‐integrin interaction mediates responses of vascular endothelial Smad1/5 and proliferation to disturbed flow
Author(s) -
Zhou J.,
Lee P.L.,
Lee C.I.,
Wei S.Y.,
Lim S. H.,
Lin T.E.,
Chien S.,
Chiu J.J.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12159
Subject(s) - microbiology and biotechnology , integrin , mapk/erk pathway , chemistry , bromodeoxyuridine , kinase , mechanotransduction , in vivo , receptor , biology , cell growth , biochemistry
Summary Background Vascular endothelial cells ( EC s) 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 EC s, 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 EC s 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 EC s at post‐stenotic sites, where disturbed flow with OSS occurs. OSS induced sustained BMPRIB ‐α v β 3 integrin association in EC s, 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 (m TOR ) and p70S6 kinase (p70S6K), a pathway critical for EC proliferation in response to OSS . Conclusions Oscillatory shear stress induces synergistic interactions between specific BMPR s and integrin to activate Smad1/5 through the Shc/ FAK / ERK pathway, which leads to the activation of the Runx2/m TOR /p70S6K pathway to promote EC proliferation.