{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhu JJ"],"funding":["HHS | National Institutes of Health","NHLBI NIH HHS","National Natural Science Foundation of China"],"pagination":["8271-8276"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5547597"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["114(31)"],"pubmed_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/cm<sup>2</sup>) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm<sup>2</sup>), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm<sup>2</sup>), 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."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia."],"pmcid":["PMC5547597"],"funding_grant_id":["81470590","HL106579","91539116","R01 HL108735","HL108735","R01 HL106579","31522022"],"pubmed_authors":["Zhao CR","Li YS","Huang TS","Yao WJ","Wang XF","Pang W","Chien S","Wang KC","Liu YF","Zhu JJ","Wang X","Zhang YP","Zhou J"],"additional_accession":[]},"is_claimable":false,"name":"VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia.","description":"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/cm<sup>2</sup>) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm<sup>2</sup>), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm<sup>2</sup>), 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.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Aug","modification":"2026-05-06T00:21:06.974Z","creation":"2019-03-26T22:59:25Z"},"accession":"S-EPMC5547597","cross_references":{"pubmed":["28716920"],"doi":["10.1073/pnas.1700561114"]}}