scholarly journals Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery–on–a–chip

2021 ◽  
Vol 7 (34) ◽  
pp. eabg1694
Author(s):  
Peng Zhao ◽  
Qingzhou Yao ◽  
Pei-Jian Zhang ◽  
Erlinda The ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Shear Stress ◽  
Coronary Artery ◽  
Single Cell ◽  
Critical Role ◽  
Three Dimensional ◽  
Human Coronary Artery ◽  
Mesenchymal Transition ◽  
Signaling Axis ◽  
Endothelial To Mesenchymal Transition

A three-dimensional microengineered human coronary artery–on–a–chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK–NF-κB signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.

MODULATION OF HUMAN CORONARY ARTERY SMOOTH MUSCLE CELLS BY SHEAR STRESS: THE ROLE OF TGF BETA1

2004 ◽  
Vol 13 (3) ◽  
pp. 190
Author(s):  
Jonathan Ghosh ◽  
David Murray ◽  
Cay Kielty ◽  
Michael Walker
Keyword(s):  
Shear Stress ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Human Coronary Artery

scholarly journals Role of Myoendothelial Gap Junctions in the Regulation of Human Coronary Artery Smooth Muscle Cell Differentiation by Laminar Shear Stress

2016 ◽  
Vol 39 (2) ◽  
pp. 423-437 ◽  
Author(s):  
Zongqi Zhang ◽  
Yizhu Chen ◽  
Tiantian Zhang ◽  
Lingyu Guo ◽  
Wenlong Yang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Gap Junctions ◽  
Phenotypic Switching ◽  
Laminar Shear Stress ◽  
Human Coronary Artery ◽  
Laminar Shear ◽  
Synthetic Phenotype

Background/Aims: Smooth muscle cells may dedifferentiate into the synthetic phenotype and promote atherosclerosis. Here, we explored the role of myoendothelial gap junctions in phenotypic switching of human coronary artery smooth muscle cells (HCASMCs) co-cultured with human coronary artery endothelial cells (HCAECs) exposed to shear stress. Methods: HCASMCs and HCAECs were seeded on opposite sides of Transwell inserts, and HCAECs were exposed to laminar shear stress of 12 dyn/cm2 or 5 dyn/cm2. The myoendothelial gap junctions were evaluated by using a multi-photon microscope. Results: In co-culture with HCAECs, HCASMCs exhibited a contractile phenotype, and maintained the expression of differentiation markers MHC and H1-calponin. HCASMCs and HCAECs formed functional intercellular junctions, as evidenced by colocalization of connexin(Cx)40 and Cx43 on cellular projections inside the Transwell membrane and biocytin transfer from HCAECs to HCASMCs. Cx40 siRNA and 18-α-GA attenuated protein expression of MHC and H1-calponin in HCASMCs. Shear stress of 5 dyn/cm2 increased Cx43 and decreased Cx40 expression in HCAECs, and partly inhibited biocytin transfer from HCAECs to HCASMCs, which could be completely blocked by Cx43 siRNA or restored by Cx40 DNA transfected into HCAECs. The exposure of HCAECs to shear stress of 5 dyn/cm2 promoted HCASMC phenotypic switching, manifested by morphological changes, decrease in MHC and H1-calponin expression, and increase in platelet-derived growth factor (PDGF)-BB release, which was partly rescued by Cx43 siRNA or Cx40 DNA or PDGF receptor signaling inhibitor. Conclusions: The exposure of HCAECs to shear stress of 5 dyn/cm2 caused the dysfunction of Cx40/Cx43 heterotypic myoendothelial gap junctions, which may be replaced by homotypic Cx43/Cx43 channels, and induced HCASMC transition to the synthetic phenotype associated with the activation of PDGF receptor signaling, which may contribute to shear stress-associated arteriosclerosis.

Comparison of Left Anterior Descending Coronary Artery Hemodynamics Before and After Angioplasty

2005 ◽  
Vol 128 (1) ◽  
pp. 40-48 ◽  
Author(s):  
S. D. Ramaswamy ◽  
S. C. Vigmostad ◽  
A. Wahle ◽  
Y.-G. Lai ◽  
M. E. Olszewski ◽  
...  
Keyword(s):  
Shear Stress ◽  
Coronary Artery ◽  
Fluid Dynamic ◽  
Critical Role ◽  
Three Dimensional ◽  
Cardiac Contraction ◽  
Local Geometry ◽  
Arbitrary Lagrangian Eulerian ◽  
Computational Fluid Dynamic Analysis ◽  
Before And After

Coronary artery disease (CAD) is characterized by the progression of atherosclerosis, a complex pathological process involving the initiation, deposition, development, and breakdown of the plaque. The blood flow mechanics in arteries play a critical role in the targeted locations and progression of atherosclerotic plaque. In coronary arteries with motion during the cardiac contraction and relaxation, the hemodynamic flow field is substantially different from the other arterial sites with predilection of atherosclerosis. In this study, our efforts focused on the effects of arterial motion and local geometry on the hemodynamics of a left anterior descending (LAD) coronary artery before and after clinical intervention to treat the disease. Three-dimensional (3D) arterial segments were reconstructed at 10 phases of the cardiac cycle for both pre- and postintervention based on the fusion of intravascular ultrasound (IVUS) and biplane angiographic images. An arbitrary Lagrangian-Eulerian formulation was used for the computational fluid dynamic analysis. The measured arterial translation was observed to be larger during systole after intervention and more out-of-plane motion was observed before intervention, indicating substantial alterations in the cardiac contraction after angioplasty. The time averaged axial wall shear stress ranged from −0.2to9.5Pa before intervention compared to −0.02to3.53Pa after intervention. Substantial oscillatory shear stress was present in the preintervention flow dynamics compared to that in the postintervention case.

Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells

Cardiology ◽  
2017 ◽  
Vol 137 (3) ◽  
pp. 179-187 ◽  
Author(s):  
Juling Feng ◽  
Jingjing Zhang ◽  
Ampadu O. Jackson ◽  
Xiao Zhu ◽  
Hainan Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Protective Effect ◽  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Apolipoprotein A1 ◽  
Human Coronary Artery ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Tgf Β1

Objective: Transforming growth factor β1 (TGF-β1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-β1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-β1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-β1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-β1-induced EndMT in human coronary artery ECs (HCAECs). Methods and Results: The HCAECs were treated with TGF-β1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-β1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-β1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-β1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-β1-induced EndMT. Conclusions: Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-β1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.

TGF-  Signaling in Endothelial-to-Mesenchymal Transition: The Role of Shear Stress and Primary Cilia

2012 ◽  
Vol 5 (212) ◽  
pp. pt2-pt2 ◽  
Author(s):  
P. ten Dijke ◽  
A. D. Egorova ◽  
M.-J. T. H. Goumans ◽  
R. E. Poelmann ◽  
B. P. Hierck
Keyword(s):  
Shear Stress ◽  
Primary Cilia ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

scholarly journals Co-Culture of Primary Human Coronary Artery and Internal Thoracic Artery Endothelial Cells Results in Mutually Beneficial Paracrine Interactions

2020 ◽  
Vol 21 (21) ◽  
pp. 8032
Author(s):  
Daria Shishkova ◽  
Victoria Markova ◽  
Maxim Sinitsky ◽  
Anna Tsepokina ◽  
Alexey Frolov ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Internal Thoracic Artery ◽  
Artery Bypass ◽  
Human Coronary Artery ◽  
Mesenchymal Transition ◽  
Gene And Protein Expression ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Homeostasis ◽  
Endothelial Nitric Oxide

Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG.

scholarly journals MiR-200c-3p promotes ox-LDL-induced endothelial to mesenchymal transition in human umbilical vein endothelial cells through SMAD7/YAP pathway

2021 ◽  
Vol 71 (1) ◽  
Author(s):  
Yongzhong Mao ◽  
Ling Jiang
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Rhodamine Phalloidin ◽  
Mesenchymal Transition ◽  
Human Umbilical Vein ◽  
Endothelial To Mesenchymal Transition ◽  
Umbilical Vein Endothelial Cells

Abstract Background Endothelial to mesenchymal transition (EndMT) participates in the progression of atherosclerosis (AS). MiR-200c-3p has been implicated in EndMT. However, the functional role of miR-200c-3p in AS remains largely unknown. Here, we demonstrated the critical role of miR-200c-3p in regulating EndMT in AS. Methods ApoE−/− mice were fed with high-fat diet to establish AS mouse model, and human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to mimic AS cell model. The expression of miR-200c-3p, SMAD7 and YAP in ApoE−/− mice and HUVECs was detected by quantitative real-time PCR. Rhodamine phalloidin staining and Western blot were performed to observe cell morphology and EndMT marker expression of HUVECs. Luciferase reporter assay and Co-Immunoprecipitation were performed to verify the relationship among miR-200c-3p, SMAD7, and YAP. Results MiR-200c-3p was highly expressed, and SMAD7 and YAP were down-regulated in the aortic tissues of ApoE−/− mice and ox-LDL-treated HUVECs. MiR-200c-3p overexpression promoted the transformation of ox-LDL-treated HUVECs from cobblestone-like epithelial phenotype to a spindle-like mesenchymal phenotype. Meanwhile, miR-200c-3p up-regulation repressed the expression of endothelial markers CD31 and vWF and promoted the expression of mesenchymal markers α-SMA and vimentin in the ox-LDL-treated HUVECs. MiR-200c-3p inhibited SMAD7 and YAP expression by interacting with 3′ untranslated region of SMAD7. Moreover, miR-200c-3p promoted EndMT in ox-LDL-treated HUVECs by inhibiting SMAD7/YAP pathway. Conclusion This work demonstrated that MiR-200c-3p promoted ox-LDL-induced EndMT in HUVECs through SMAD7/YAP pathway, which may be important for the onset of atherosclerosis.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Maria Cecilia Oliveira-Nunes ◽  
Glaucia Julião ◽  
Aline Menezes ◽  
Fernanda Mariath ◽  
John A. Hanover ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Critical Role ◽  
Molecular Signature ◽  
Label Free ◽  
Intercellular Signaling ◽  
Tumor Aggressiveness ◽  
Signaling Axis ◽  
Literature Evidence ◽  
Therapeutic Tools

AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.

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