https://scholars.lib.ntu.edu.tw/handle/123456789/468517
Title: | Force-specific activation of Smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow | Authors: | Zhou J. Lee P.-L. Tsai C.-S. Lee C.-I. Yang T.-L. Chuang H.-S. Lin W.-W. Lin T.-E. Lim S.H. Wei S.-Y. YUH-LIEN CHEN Chien S. Chiu J.-J. |
Issue Date: | 2012 | Journal Volume: | 109 | Journal Issue: | 20 | Start page/Pages: | 7770-7775 | Source: | Proceedings of the National Academy of Sciences of the United States of America | Abstract: | Vascular endothelial cells (ECs) are constantly exposed to blood flow-induced shear stress, but the mechanism of force-specific activation of their signaling to modulate cellular function remains unclear. We have demonstrated that bone morphogenetic protein receptor (BMPR)-specific Smad1/5 can be force-specifically activated by oscillatory shear stress (OSS) in ECs to cause cell cycle progression. Smad1/5 is highly activated in ECs of atherosclerotic lesions in diseased human coronary arteries from patients with end-stage heart failure undergoing heart transplantation and from apolipoprotein E-deficient mice. Application of OSS (0.5 ± 4 dyn/cm2) causes the sustained activation of Smad1/5 in ECs through activations of mammalian target of rapamycin and p70S6 kinase, leading to up-regulation of cyclin A and down-regulations of p21CIP1 and p27KIP1 and, hence, EC cycle progression. En face examination of rat aortas reveals high levels of phospho-Smad1/5 in ECs of the straight segment of thoracic aorta and the inner, but not the outer, curvature of aortic arch. Immunohistochemical and en face examinations of the experimentally stenosed abdominal aorta in rats show high levels of phospho-Smad1/5 in ECs at poststenotic sites, where OSS occurs. These OSS activations of EC Smad1/5 in vitro and in vivo are not inhibited by the BMP-specific antagonist Noggin and, hence, are independent of BMP ligand. Transfecting ECs with Smad1/5-specific small interfering RNAs inhibits the OSS-induced EC cycle progression. Our findings demonstrate the force-specificity of the activation of Smad1/5 and its contribution to cell cycle progression in ECs induced by disturbed flow. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84861220379&doi=10.1073%2fpnas.1205476109&partnerID=40&md5=4e4621fe962375c16766b4426c4bab36 https://scholars.lib.ntu.edu.tw/handle/123456789/468517 |
ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1205476109 | SDG/Keyword: | apolipoprotein E; cyclin A; cyclin dependent kinase inhibitor 1; cyclin dependent kinase inhibitor 1B; ligand; mammalian target of rapamycin; noggin; Smad1 protein; Smad5 protein; small interfering RNA; abdominal aorta; animal experiment; animal model; animal tissue; aorta arch; article; atherosclerosis; cell cycle progression; controlled study; coronary artery disease; down regulation; endothelium cell; flow kinetics; force; heart failure; heart transplantation; human; human cell; immunohistochemistry; in vitro study; in vivo study; mouse; nonhuman; priority journal; protein function; shear stress; thoracic aorta; upregulation; vascular endothelium; Animals; Aorta, Abdominal; Apolipoproteins E; Atherosclerosis; Biomechanics; Cell Cycle; Coronary Vessels; Cyclin A; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Endothelial Cells; Gene Expression Regulation; Humans; Immunohistochemistry; Mice; Mice, Knockout; Rats; Regional Blood Flow; Ribosomal Protein S6 Kinases, 70-kDa; Smad1 Protein; Stress, Mechanical; Taiwan; TOR Serine-Threonine Kinases; Mammalia; Mus; Rattus |
Appears in Collections: | 解剖學暨細胞生物學科所 |
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