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Mechanical Activation of Smad, A Novel Regulator for Endothelial Cell Proliferation Induced by Disturbed Flow
Author(s) -
Zhou Jing,
Lee PeiLing,
Lee ChihI,
Yang TungLin,
Chien Shu,
Chiu JengJiann
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.598.12
Subject(s) - noggin , smad , umbilical vein , microbiology and biotechnology , integrin , cell growth , chemistry , kinase , regulator , phosphorylation , cell , bone morphogenetic protein , biology , biochemistry , in vitro , gene
Atherosclerotic lesions develop at arterial branches and curvatures, where the local flow is disturbed with low and oscillatory shear stress (OSS). We investigated the role of OSS in the endothelial cell (EC) activations of Smad1/5 and their regulation in OSS‐induced EC proliferation. OSS (0.5±4 dynes/cm 2 ) to human umbilical vein ECs induced sustained phosphorylations of Smad1/5. Smad1/5 activations were found only in the selective patches of ECs overlying foam cell lesions in human coronary arteries. These shear‐activations of Smad1/5 were not inhibited by pre‐treating ECs with Noggin, a specific antagonist of bone morphogenic proteins. Transfecting ECs with specific siRNA of BMPRII, BMPRIB, and α v and β 3 integrins inhibited OSS‐induced Smad1/5 phosphorylations. OSS induced sustained increases in the association of α v β 3 integrin with BMPRIB, which was inhibited by BMPRII‐specific siRNA. OSS induced the activations of focal adhesion kinase/Shc/extracellular signal‐regulated kinase, which are required for OSS‐induced Smad1/5 phosphorylations. OSS induced increased expression of cyclin A and decreased expressions of p21 CIP1 and p27 KIP1 and hence proliferation in ECs. Transfecting ECs with Smad1/5‐specific siRNA inhibited these OSS‐induced responses in ECs. Our findings provide a molecular basis for the role of Smad1/5 in regulating EC proliferation in response to OSS.