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

2017 ◽  
Vol 114 (31) ◽  
pp. 8271-8276 ◽  
Author(s):  
Juan-Juan Zhu ◽  
Yue-Feng Liu ◽  
Yun-Peng Zhang ◽  
Chuan-Rong Zhao ◽  
Wei-Juan Yao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Flow Pattern ◽  
Vascular Endothelial Cells ◽  
Mammalian Target Of Rapamycin ◽  
Pharmacological Intervention ◽  
Neointimal Formation ◽  
Disturbed Flow ◽  
Transcriptional Inhibition ◽  
Muscle Hyperplasia ◽  
Smooth Muscle Hyperplasia

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.

Abstract 162: MicroRNAs Mediate the Hemodynamic Regulation of Endothelium-to-Smooth Muscle Signaling

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jing Zhou ◽  
Juanjuan Zhu ◽  
Yuefeng Liu ◽  
Shu Chien
Keyword(s):  
Smooth Muscle ◽  
Flow Pattern ◽  
Vascular Endothelial Cells ◽  
Vascular Diseases ◽  
Therapeutic Interventions ◽  
Pharmacological Intervention ◽  
Neointimal Formation ◽  
Transcriptional Inhibition ◽  
Protein Receptors ◽  
Phenotypic Transition

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 has 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 (LS) to ECs. In the current study we found that atherogenic oscillatory shear (OS), but not atheroprotective pulsatile shear (PS), promotes the regulated exocytosis, particularly the secretion of non-membrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of soluble N-ethyl-maleimide-sensitive fusion protein attachment protein receptors (SNAREs), VAMP3 and SNAP23. Quantitative PCR arrays identify 15 EC-secreted miRNAs whose levels in the vesicle-poor supernatant of flow perfusate are differentially regulated (P<0.05) by OS versus PS. The fold changes of 11 miRNAs are either greater than 2.0 or less than 0.5. Knockdown of VAMP3 and SNAP23 reduces the 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 mTORC1 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 SNAREs activation and its contribution to the miRNA-mediated EC-SMC communication, uncovering potential targets for future diagnosis and therapeutic interventions for proliferative vascular diseases.

Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation

2021 ◽  
Vol 118 (48) ◽  
pp. e2115158118
Author(s):  
Chuan-Rong Zhao ◽  
Fang-Fang Yang ◽  
Qinghua Cui ◽  
Dong Wang ◽  
Yiran Zhou ◽  
...  
Keyword(s):  
Laminar Flow ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cells ◽  
Animal Experiments ◽  
Shear Stresses ◽  
Neointimal Formation ◽  
Disturbed Flow ◽  
Endothelial Inflammation ◽  
Therapeutic Molecules ◽  
Factor Α

Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.

scholarly journals Neointimal hyperplasia regression using combined paclitaxel- mediated confocal dual pulse shock wave sonoporation therapy and catheter- based 90Y- mediated brachytherapy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
H Mehrad
Keyword(s):  
Shock Wave ◽  
Smooth Muscle ◽  
Treatment Group ◽  
Neointimal Hyperplasia ◽  
Balloon Catheter ◽  
Public Institution ◽  
Cavitation Effect ◽  
Muscle Hyperplasia ◽  
Smooth Muscle Hyperplasia ◽  
Tunica Intima

Abstract Background and aims Intimal hyperplasia refers to proliferation and migration of vascular smooth muscle cells primarily in the tunica intima, resulting in arterial wall thickening and decreased arterial lumen size. Neointimal hyperplasia is the major cause of restenosis after percutaneous carotid interventions such as stenting or angioplasty. The aim of this study was to investigate the effect of combined shock wave enhanced sonoporation therapy and catheter-based 90Y-mediated β-brachytherapy on neointimal hyperplasia regression in an animal model, wherein diagnostic B-mode ultrasound is combined with therapy system, with a goal of increased safety. Methods Endothelial balloon catheter denudation of the abdominal aorta of golden Syrian hamsters was performed. Histopathologic evaluation confirmed neointimal hyperplasia formation in all of the hamsters' arteries. The treatment group underwent intravenous lipid-based encapsulated paclitaxel nanoparticles (10mg/kg)-mediated extracorporeal confocal dual pulse low-level focused electrohydraulic shock wave (V=15 kV, F=2 Hz, Impulses = 50 and V=10 kV, F=0.2 Hz, Impulses = 150) enhanced sonoporation therapy accompanied by catheter-based 90Y-mediated β-brachytherapy (90Y, 15 Gy), guided by simultaneous B-mode ultrasound imaging. Results B-mode ultrasound guided combined shock wave enhanced sonoporation therapy and β-brachytherapy was feasible and appeared safe for the targeting of stenosis in the aorta artery. Furthermore, pathological results showed a significant reduction in the mean value for smooth muscle hyperplasia cells density, lumen wall thickness and percentage of luminal cross- sectional area of stenosis in the treatment group compared with the other groups (p&lt;0.05). Conclusions Enhanced toxicity effect of paclitaxel, induced by enhanced sonoporation effect of shock wave therapy, due to inertial cavitation effect of collapsed capsules and dual pulse system application accompanied by apoptotic effect of brachytherapy, can cause to neointimal hyperplasia regression. Combined shock wave enhanced sonoporation therapy and β-brachytherapy is significantly associated with reduced aorta artery stenosis in hamsters. The mechanism may relate to reduced smooth muscle hyperplasia cells and inflammation in the tunica intima. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

scholarly journals Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

2018 ◽  
Vol 32 (9) ◽  
pp. 5174-5185 ◽  
Author(s):  
Himanshu Sharma ◽  
Mahendran Chinnappan ◽  
Stuti Agarwal ◽  
Pranjali Dalvi ◽  
Sumedha Gunewardena ◽  
...  
Keyword(s):  
Substance Abuse ◽  
Smooth Muscle ◽  
Hiv Infection ◽  
Extracellular Vesicles ◽  
Muscle Hyperplasia ◽  
Smooth Muscle Hyperplasia

Sonographic Findings of Smooth Muscle Hyperplasia of the Epididymis

2009 ◽  
Vol 28 (7) ◽  
pp. 963-965 ◽  
Author(s):  
Dal Mo Yang ◽  
Hyun Cheol Kim ◽  
Hyung Lae Lee ◽  
Gyo Young Kim
Keyword(s):  
Smooth Muscle ◽  
Muscle Hyperplasia ◽  
Smooth Muscle Hyperplasia

scholarly journals Endogenous IGF-I and αvβ3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

2009 ◽  
Vol 296 (6) ◽  
pp. G1230-G1237 ◽  
Author(s):  
Krystina B. Hazelgrove ◽  
Robert S. Flynn ◽  
Li-Ya Qiao ◽  
John R. Grider ◽  
John F. Kuemmerle
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Muscle Cell ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Intestinal Smooth Muscle ◽  
Muscle Hyperplasia ◽  
Igf I ◽  
Integrin Ligands ◽  
Smooth Muscle Hyperplasia

Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the αvβ3 integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although αvβ3 integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 ± 10% and 90 ± 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 ± 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3β phosphorylation in muscle cells of TNBS-treated rats were also increased by 140–180%. TNBS treatment increased basal muscle cell proliferation by 130 ± 15% and decreased apoptosis by 20 ± 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an αvβ3 integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of αvβ3 integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

scholarly journals Angiopoietin/Tie2 Pathway Influences Smooth Muscle Hyperplasia in Idiopathic Pulmonary Hypertension

2006 ◽  
Vol 174 (9) ◽  
pp. 1025-1033 ◽  
Author(s):  
Laurence Dewachter ◽  
Serge Adnot ◽  
Elie Fadel ◽  
Marc Humbert ◽  
Bernard Maitre ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Muscle Hyperplasia ◽  
Idiopathic Pulmonary Hypertension ◽  
Smooth Muscle Hyperplasia
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