title: Force-specific activation of Smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow.
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/cm(2)) 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 p21(CIP1) and p27(KIP1) and, hence, EC cycle progression. En face examination of rat aortas reveals high levels of phospho-Smad1/5 in ECs of the inner, but not the outer, curvature of aortic arch, nor the straight segment of thoracic aorta [corrected]. 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.
authors.affiliation: Division of Medical Engineering Research,  National Health Research Institutes, Miaoli 350,  Taiwan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Lee
authors.forename: Chien-Sung
authors.initials: CS
authors.lastname: Tsai
authors.forename: Chih-I
authors.initials: CI
authors.lastname: Lee
authors.forename: Tung-Lin
authors.initials: TL
authors.lastname: Yang
authors.forename: Han-Sheng
authors.initials: HS
authors.lastname: Chuang
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Lin
authors.forename: Ting-Er
authors.initials: TE
authors.lastname: Lin
authors.forename: Seh Hong
authors.initials: SH
authors.lastname: Lim
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Wei
authors.forename: Yuh-Lien
authors.initials: YL
authors.lastname: Chen
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D002453:Cell Cycle / Q000502:physiology*; D003331:Coronary Vessels / Q000166:cytology / Q000473:pathology; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D012039:Regional Blood Flow / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D051898:Smad1 Protein / Q000378:metabolism*; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013624:Taiwan
chemical_list: D001057:Apolipoproteins E; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases