scholarly journals Extracellular Vesicles Containing MicroRNA-92a-3p Facilitate Partial Endothelial-Mesenchymal Transition and Angiogenesis in Endothelial Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4406 ◽  
Author(s):  
Nami O. Yamada ◽  
Kazuki Heishima ◽  
Yukihiro Akao ◽  
Takao Senda
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Epithelial To Mesenchymal Transition ◽  
Ectopic Expression ◽  
Cell Communication ◽  
Related Gene ◽  
Mesenchymal Transition ◽  
Essential Components ◽  
Endothelial To Mesenchymal Transition

Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.

scholarly journals Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Ouafa Hamza ◽  
Attila Kiss ◽  
Anne-Margarethe Kramer ◽  
Sandra Trojanek ◽  
Dietmar Abraham ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mitral Regurgitation ◽  
Epithelial To Mesenchymal Transition ◽  
Ischemic Mitral Regurgitation ◽  
Large Animal ◽  
Mesenchymal Transition ◽  
Mitral Valves ◽  
Tenascin C ◽  
Large Animal Models ◽  
Endothelial To Mesenchymal Transition

AbstractIschemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p < 0.001 at 6 weeks, R = 0.84; p < 0.001 at 6 months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (n = 5). Indeed, TNC was also expressed in the mitral leaflets of these. Furthermore, TNC induced EMT in isolated porcine mitral valve endothelial cells (MVEC). Interestingly, Toll-like receptor 4 (TLR4) inhibition prevented TNC-mediated EMT in MVEC. We identified here for the first time a new contributor to valvular remodeling in ischemic MR, namely TNC, which induced EMT through TLR4. Our findings might set the path for novel therapeutic targets for preventing or limiting ischemic MR.

scholarly journals Seamless Genetic Recording of Transiently Activated Mesenchymal Gene Expression in Endothelial Cells During Cardiac Fibrosis

Circulation ◽  
2021 ◽  
Author(s):  
Shaohua Zhang ◽  
Yan Li ◽  
Xiuzhen Huang ◽  
Kuo Liu ◽  
Qing-Dong Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Fibrosis ◽  
Marker Gene ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Mesenchymal Transition ◽  
Heart Injury

Background: Cardiac fibrosis is a lethal outcome of excessive formation of myofibroblasts that are scar-forming cells accumulated after heart injury. It has been reported that cardiac endothelial cells (ECs) contribute to a substantial portion of myofibroblasts through EndoMT. Recent lineage tracing studies demonstrate that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation of ECs. However, it remains unknown whether ECs can transdifferentiate into myofibroblasts reversibly or EndoMT genes were just transiently activated in ECs during cardiac fibrosis. Methods: By using the dual recombination technology based on Cre-loxP and Dre-rox, we generated a genetic lineage tracing system for tracking EndoMT in cardiac ECs. We used it to examine if there is transiently activated mesenchymal gene expression in ECs during cardiac fibrosis. Activation of the broadly used marker gene in myofibroblasts, αSMA, and the transcription factor that induces epithelial to mesenchymal transition (EMT), Zeb1, was examined. Results: The genetic system enables continuous tracing of transcriptional activity of targeted genes in vivo . Our genetic fate mapping results revealed that a subset of cardiac ECs transiently expressed αSMA and Zeb1 during embryonic valve formation and transdifferentiated into mesenchymal cells through EndoMT. Nonetheless, they did not contribute to myofibroblasts; nor transiently expressed αSMA or Zeb1 after heart injury. Instead, expression of αSMA was activated in resident fibroblasts during cardiac fibrosis. Conclusions: Mesenchymal gene expression is activated in cardiac ECs through EndoMT in the developing heart; but ECs do not transdifferentiate into myofibroblasts, nor transiently express some known mesenchymal genes during homeostasis and fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblasts by activating mesenchymal gene expression are the major contributors to cardiac fibrosis.

scholarly journals Efficient hemogenic endothelial cell specification by RUNX1 is dependent on baseline chromatin accessibility of RUNX1-regulated TGFβ target genes

2021 ◽  
Author(s):  
Elizabeth D. Howell ◽  
Amanda D. Yzaguirre ◽  
Peng Gao ◽  
Raphael Lis ◽  
Bing He ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Target Genes ◽  
De Novo ◽  
Ectopic Expression ◽  
Chromatin Accessibility ◽  
Tgfβ Signaling ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Stem And Progenitor Cells ◽  
Endothelial To Mesenchymal Transition

Hematopoietic stem and progenitor cells (HSPCs) are generated de novo in the embryo from hemogenic endothelial cells (HECs) via an endothelial-to-hematopoietic transition (EHT) that requires the transcription factor RUNX1. Ectopic expression of RUNX1 alone can efficiently promote EHT and HSPC formation from embryonic endothelial cells (ECs), but less efficiently from fetal or adult ECs. Efficiency correlated with baseline accessibility of TGFβ-related genes associated with endothelial-to-mesenchymal transition (EndoMT) and participation of AP-1 and SMAD2/3 to initiate further chromatin remodeling along with RUNX1 at these sites. Activation of TGFβ signaling improved the efficiency with which RUNX1 specified fetal ECs as HECs. Thus, the ability of RUNX1 to promote EHT depends on its ability to recruit the TGFβ signaling effectors AP-1 and SMAD2/3, which in turn is determined by the changing chromatin landscape in embryonic versus fetal ECs. This work provides insight into regulation of EndoMT and EHT that will guide reprogramming efforts for clinical applications.

scholarly journals Involvement of Extracellular Vesicles in Vascular-Related Functions in Cancer Progression and Metastasis

2019 ◽  
Vol 20 (10) ◽  
pp. 2584 ◽  
Author(s):  
Shinsuke Kikuchi ◽  
Yusuke Yoshioka ◽  
Marta Prieto-Vila ◽  
Takahiro Ochiya
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Cell Communication ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Patients With Cancer ◽  
Tumor Environment ◽  
Endothelial To Mesenchymal Transition

The primary cause of mortality among patients with cancer is the progression of the tumor, better known as cancer invasion and metastasis. Cancer progression involves a series of biologically important steps in which the cross-talk between cancer cells and the cells in the surrounding environment is positioned as an important issue. Notably, angiogenesis is a key tumorigenic phenomenon for cancer progression. Cancer-related extracellular vesicles (EVs) commonly contribute to the modulation of a microenvironment favorable to cancer cells through their function of cell-to-cell communication. Vascular-related cells such as endothelial cells (ECs) and platelets activated by cancer cells and cancer-derived EVs develop procoagulant and proinflammatory statuses, which help excite the tumor environment, and play major roles in tumor progression, including in tumor extravasation, tumor cell microthrombi formation, platelet aggregation, and metastasis. In particular, cancer-derived EVs influence ECs, which then play multiple roles such as contributing to tumor angiogenesis, loss of endothelial vascular barrier by binding to ECs, and the subsequent endothelial-to-mesenchymal transition, i.e., extracellular matrix remodeling. Thus, cell-to-cell communication between cancer cells and ECs via EVs may be an important target for controlling cancer progression. This review describes the current knowledge regarding the involvement of EVs, especially exosomes derived from cancer cells, in EC-related cancer progression.

scholarly journals Extracellular Vesicles Are Key Regulators of Tumor Neovasculature

2020 ◽  
Vol 8 ◽  
Author(s):  
Naoya Kuriyama ◽  
Yusuke Yoshioka ◽  
Shinsuke Kikuchi ◽  
Nobuyoshi Azuma ◽  
Takahiro Ochiya
Keyword(s):  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Current Knowledge ◽  
Cell Communication ◽  
Multiple Roles ◽  
Mesenchymal Transition ◽  
Surrounding Environment ◽  
Endothelial To Mesenchymal Transition ◽  
Review Current

Tumor progression involves a series of biologically important steps in which the crosstalk between cancer cells and the surrounding environment is an important issue. Angiogenesis is a key tumorigenic phenomenon for cancer progression. Tumor-related extracellular vesicles (EVs) modulate the tumor microenvironment (TME) through cell-to-cell communication. Tumor cells in a hypoxic TME release more EVs than cells in a normoxic environment due to uncontrollable tumor proliferation. Tumor-derived EVs in the TME influence endothelial cells (ECs), which then play multiple roles, contributing to tumor angiogenesis, loss of the endothelial vascular barrier by binding to ECs, and subsequent endothelial-to-mesenchymal transition. In contrast, they also indirectly induce tumor angiogenesis through the phenotype switching of various cells into cancer-associated fibroblasts, the activation of tumor-associated ECs and platelets, and remodeling of the extracellular matrix. Here, we review current knowledge regarding the involvement of EVs in tumor vascular-related cancer progression.

scholarly journals Transcriptomic profiling and pathway analysis of cultured human lung microvascular endothelial cells following ionizing radiation exposure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Roxane M. Bouten ◽  
Clifton L. Dalgard ◽  
Anthony R. Soltis ◽  
John E. Slaven ◽  
Regina M. Day
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Endothelial Cells ◽  
Dna Damage Response ◽  
Human Lung ◽  
Microvascular Endothelial Cells ◽  
Mesenchymal Transition ◽  
Damage Response ◽  
Endothelial To Mesenchymal Transition

AbstractThe vascular system is sensitive to radiation injury, and vascular damage is believed to play a key role in delayed tissue injury such as pulmonary fibrosis. However, the response of endothelial cells to radiation is not completely understood. We examined the response of primary human lung microvascular endothelial cells (HLMVEC) to 10 Gy (1.15 Gy/min) X-irradiation. HLMVEC underwent senescence (80–85%) with no significant necrosis or apoptosis. Targeted RT-qPCR showed increased expression of genes CDKN1A and MDM2 (10–120 min). Western blotting showed upregulation of p2/waf1, MDM2, ATM, and Akt phosphorylation (15 min–72 h). Low levels of apoptosis at 24–72 h were identified using nuclear morphology. To identify novel pathway regulation, RNA-seq was performed on mRNA using time points from 2 to 24 h post-irradiation. Gene ontology and pathway analysis revealed increased cell cycle inhibition, DNA damage response, pro- and anti- apoptosis, and pro-senescence gene expression. Based on published literature on inflammation and endothelial-to-mesenchymal transition (EndMT) pathway genes, we identified increased expression of pro-inflammatory genes and EndMT-associated genes by 24 h. Together our data reveal a time course of integrated gene expression and protein activation leading from early DNA damage response and cell cycle arrest to senescence, pro-inflammatory gene expression, and endothelial-to-mesenchymal transition.

scholarly journals SOX9 is sufficient to drive endothelial cells towards a mesenchymal fate by altering the chromatin landscape

2020 ◽  
Author(s):  
Bettina M. Fuglerud ◽  
Sibyl Drissler ◽  
Tabea L. Stephan ◽  
Avinash Thakur ◽  
Rebecca Cullum ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Enhancer Activity ◽  
Mesenchymal Transition ◽  
Specific Subset ◽  
Pioneer Transcription Factor ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Genes

AbstractThe transcription factor SOX9 is expressed in multiple tissues during embryogenesis and directs developmental processes. SOX9 is activated upon epithelial-to-mesenchymal transition (EMT) and the closely related process, endothelial-to-mesenchymal transition (EndMT), but its role in regulating these processes is less clear. Both EMT and EndMT are fundamental processes in normal development and cancer progression. Here, we show that SOX9 expression alone is sufficient to activate mesenchymal enhancers and steer endothelial cells towards a mesenchymal fate. By genome-wide mapping of the chromatin landscape, we show that SOX9 acts as a pioneer transcription factor, having the ability to open the chromatin structure and increase enrichment of active histone marks at a specific subset of target enhancers with an associated SOX motif. SOX9 also displays widespread chromatin pausing that is not associated with SOX motifs. This leads to a switch in enhancer activity states resulting in activation of mesenchymal genes and concurrent suppression of endothelial genes to drive EndMT. Moreover, SOX9 induced widespread changes in chromatin states throughout the genome without SOX9 binding. Our study highlights the crucial developmental role of SOX9 and provides new insight into key molecular functions of SOX9 in regulating the chromatin landscape and mechanisms of EndMT.

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