Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair.
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.
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.
Farima
F
Zahedi
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802, Munich, Germany.
Maliheh
M
Nazari-Jahantigh
Institute for Molecular Cardiovascular Research, RWTH Aachen University, 52074, Aachen, Germany.|The Genomics Center of AMMS, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
Zhe
Z
Zhou
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.|Department of Clinical Pathobiochemistry, University Clinic Carl Gustav Carus, Dresden University of Technology, 01307, Dresden, Germany.
Pallavi
P
Subramanian
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802, Munich, Germany.
Yuanyuan
Y
Wei
European Vascular Center Aachen-Maastricht, Medical University Maastricht, 6229 HX, Maastricht, The Netherlands.|European Vascular Center Aachen-Maastricht, RWTH Aachen University, 52074, Aachen, Germany.
Jochen
J
Grommes
Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
Stefan
S
Offermanns
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802, Munich, Germany.
Sabine
S
Steffens
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802, Munich, Germany.
Christian
C
Weber
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336, Munich, Germany. aschober@med.lmu.de.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802, Munich, Germany. aschober@med.lmu.de.|Institute for Molecular Cardiovascular Research, RWTH Aachen University, 52074, Aachen, Germany. aschober@med.lmu.de.
Andreas
0000-0001-7798-136X
A
Schober
D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*
D035683:MicroRNAs; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; D043244:Ribonuclease III
ARHGEF26; Cell proliferation; Dicer; MicroRNA; Smooth muscle cells