Cellular and Molecular Life Sciences

, Volume 74, Issue 2, pp 359–372 | Cite as

Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair

  • Farima Zahedi
  • Maliheh Nazari-Jahantigh
  • Zhe Zhou
  • Pallavi Subramanian
  • Yuanyuan Wei
  • Jochen Grommes
  • Stefan Offermanns
  • Sabine Steffens
  • Christian Weber
  • Andreas SchoberEmail author
Original Article


MicroRNAs (miRNAs) coordinate vascular repair by regulating injury-induced gene expression in vascular smooth muscle cells (SMCs) and promote the transition of SMCs from a contractile to a proliferating phenotype. However, the effect of miRNA expression in SMCs on neointima formation is unclear. Therefore, we studied the role of miRNA biogenesis by Dicer in SMCs in vascular repair. Following wire-induced injury to carotid arteries of Apolipoprotein E knockout (Apoe /) mice, miRNA microarray analysis revealed that the most significantly regulated miRNAs, such as miR-222 and miR-21-3p, were upregulated. Conditional deletion of Dicer in SMCs increased neointima formation by reducing SMC proliferation in Apoe / mice, and decreased mainly the expression of miRNAs, such as miR-147 and miR-100, which were not upregulated following vascular injury. SMC-specific deletion of Dicer promoted growth factor and inflammatory signaling and regulated a miRNA–target interaction network in injured arteries that was enriched in anti-proliferative miRNAs. The most connected miRNA in this network was miR-27a-3p [e.g., with Rho guanine nucleotide exchange factor 26 (ARHGEF26)], which was expressed in medial and neointimal SMCs in a Dicer-dependent manner. In vitro, miR-27a-3p suppresses ARHGEF26 expression and inhibits SMC proliferation by interacting with a conserved binding site in the 3′ untranslated region of ARHGEF26 mRNA. We propose that Dicer expression in SMCs plays an essential role in vascular repair by generating anti-proliferative miRNAs, such as miR-27a-3p, to prevent vessel stenosis due to exaggerated neointima formation.


MicroRNA Dicer Smooth muscle cells Cell proliferation ARHGEF26 



Apolipoprotein E


Rho guanine nucleotide exchange factor 26


Carbohydrate (keratan sulfate Gal-6) sulfotransferase 1




Delta-like 4


Dulbecco′s modified eagle medium


Endothelial cell


Epidermal growth factor


Human aortic smooth muscle cell


Human embryonic kidney 293 cell


High-fat diet


Insulin-like growth-factor-binding protein 3






Locked nucleic acid


miRNA, miR


Myosin, heavy chain 11, smooth muscle


Nuclear factor of kappa light polypeptide gene enhancer in B-cells


Oncoprotein-induced transcript 3


Platelet-derived growth factor


miRNA-induced-silencing complex


SH3-domain-binding glutamate-rich protein-like 2


Smooth muscle actin


Smooth muscle cell




Tumor necrosis factor α


Argonaute and trinucleotide repeat containing 6A


Target site blocker


Untranslated region


Wild type



This work has been funded by the German Research Foundation (DFG) as part of the Collaborative Research Center 1123 (B04) and by the German Center for Cardiovascular Research (MHA VD1.2). The authors declare no competing financial interests.

Supplementary material

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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Farima Zahedi
    • 1
  • Maliheh Nazari-Jahantigh
    • 1
    • 2
  • Zhe Zhou
    • 3
    • 7
  • Pallavi Subramanian
    • 1
    • 8
  • Yuanyuan Wei
    • 1
    • 2
  • Jochen Grommes
    • 4
    • 5
  • Stefan Offermanns
    • 6
  • Sabine Steffens
    • 1
    • 2
  • Christian Weber
    • 1
    • 2
  • Andreas Schober
    • 1
    • 2
    • 3
    Email author
  1. 1.Institute for Cardiovascular PreventionLudwig-Maximilians-University MunichMunichGermany
  2. 2.DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart AllianceMunichGermany
  3. 3.Institute for Molecular Cardiovascular ResearchRWTH Aachen UniversityAachenGermany
  4. 4.European Vascular Center Aachen-MaastrichtMedical University MaastrichtMaastrichtThe Netherlands
  5. 5.European Vascular Center Aachen-MaastrichtRWTH Aachen UniversityAachenGermany
  6. 6.Max Planck Institute for Heart and Lung ResearchBad NauheimGermany
  7. 7.The Genomics Center of AMMSBeijing Institute of Radiation MedicineBeijingPeople’s Republic of China
  8. 8.Department of Clinical PathobiochemistryUniversity Clinic Carl Gustav Carus, Dresden University of TechnologyDresdenGermany

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