1. VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia
- Author
-
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, and Zhou, Jing
- Subjects
Biotechnology ,Atherosclerosis ,Cardiovascular ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Endothelial Cells ,Humans ,Hyperplasia ,Mice ,Mice ,Knockout ,MicroRNAs ,Muscle ,Smooth ,Vascular ,Myocytes ,Smooth Muscle ,Qb-SNARE Proteins ,Qc-SNARE Proteins ,SNARE Proteins ,Vesicle-Associated Membrane Protein 3 ,endothelial cells ,shear stress ,SNAREs ,extracellular microRNA ,neointimal formation - 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.
- Published
- 2017