Force-specific activation of Smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow

Jing Zhou, Pei Ling Lee, Chien Sung Tsai, Chih I. Lee, Tung Lin Yang, Han Sheng Chuang, Wei Wen Lin, Ting Er Lin, Seh Hong Lim, Shu Yi Wei, Yuh Lien Chen, Shu Chien, Jeng Jiann Chiu

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51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7770-7775
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number20
DOIs
Publication statusPublished - May 15 2012
Externally publishedYes

Keywords

  • Atherosclerosis
  • Stenosis

ASJC Scopus subject areas

  • General

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  • Cite this

    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., Chen, Y. L., Chien, S., & Chiu, J. J. (2012). Force-specific activation of Smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow. Proceedings of the National Academy of Sciences of the United States of America, 109(20), 7770-7775. https://doi.org/10.1073/pnas.1205476109