Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126 role of shear stress

Jing Zhou, Yi Shuan Li, Phu Nguyen, Kuei Chun Wang, Anna Weiss, Yi Chun Kuo, Jeng Jiann Chiu, John Y. Shyy, Shu Chien

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136 Citations (Scopus)

Abstract

Rationale: Endothelial microRNA-126 (miR-126) modulates vascular development and angiogenesis. However, its role in the regulation of smooth muscle cell (SMC) function is unknown. Objective: To elucidate the role of miR-126 secreted by endothelial cells (ECs) in regulating SMC turnover in vitro and in vivo, as well as the effects of shear stress on the regulation. Methods and Results: Coculture of SMCs with ECs or treatment of SMCs with conditioned media from static EC monoculture (EC-CM) increased SMC miR-126 level and SMC turnover; these effects were abolished by inhibition of endothelial miR-126 and by the application of laminar shear stress to ECs. SMC miR-126 did not increase when treated with EC-CM from ECs subjected to inhibition of miR biogenesis, or with CM from sheared ECs. Depletion of extracellular/secreted vesicles in EC-CM did not affect the increase of SMC miR-126 by EC-CM. Biotinylated miR-126 or FLAG (DYKDDDDK epitope)-tagged Argonaute2 transfected into ECs was detected in the cocultured or EC-CM-treated SMCs, indicating a direct EC-to-SMC transmission of miR-126 and Argonaute2. Endothelial miR-126 represses forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 mRNAs in the cocultured SMCs, suggesting the functional roles of the transmitted miR-126. Systemic depletion of miR-126 in mice inhibited neointimal lesion formation of carotid arteries induced by cessation of blood flow. Administration of EC-CM or miR-126 mitigated the inhibitory effect. Conclusions: Endothelial miR-126 acts as a key intercellular mediator to increase SMC turnover, and its release is reduced by atheroprotective laminar shear stress. (Circ Res. 2013;113:40-51.).

Original languageEnglish
Pages (from-to)40-51
Number of pages12
JournalCirculation Research
Volume113
Issue number1
DOIs
Publication statusPublished - Jun 1 2013
Externally publishedYes

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Keywords

  • Atherosclerosis
  • Endothelial cell
  • Extracellular miR-126
  • Shear stress
  • Smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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