VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Juan Juan Zhu, Yue Feng Liu, Yun Peng Zhang, Chuan Rong Zhao, Wei Juan Yao, Yi Shuan Li, Kuei Chun Wang, Tse Shun Huang, Wei Pang, Xi Fu Wang, Xian Wang, Shu Chien, Jing Zhou

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm2) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm2), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm2), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern–specificity of SNARE activation and its contribution to the miRNA-mediated EC–SMC communication.

Original languageEnglish (US)
Pages (from-to)8271-8276
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number31
DOIs
StatePublished - Aug 1 2017

Keywords

  • Endothelial cells
  • Extracellular microRNA
  • Neointimal formation
  • SNAREs
  • Shear stress

ASJC Scopus subject areas

  • General

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