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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-08, Vol.114 (31), p.8271-8276
• Main Authors: Zhu, Juan-Juan, Liu, Yue-Feng, Zhang, Yun-Peng, Zhao, Chuan-Rong, Yao, Wei-Juan, Li, Yi-Shuan, Wang, Kuei-Chun, Huang, Tse-Shun, Pang, Wei, Wang, Xi-Fu, Wang, Xian, Chien, Shu, Zhou, Jing
• Format: Article
• Language: English
• Subjects: Activation; Biological Sciences; Blood flow; Endocytosis; Endothelial cells; Endothelium; Genotype & phenotype; Hyperplasia; Inhibition; Membrane proteins; MicroRNAs; miRNA; Muscle contraction; Muscular system; Pharmacology; Proteins; Rapamycin; Ribonucleic acid; RNA; Secretion; Shear; Signal transduction; Smooth muscle; SNAP receptors; TOR protein; Transcription
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1700561114

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 ofmiR-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.