scholarly journals The uptake of trimethylamine N-oxide (TMAO) and its influence on endothelial cell identity and inflammation

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Rittig ◽  
L Gaal ◽  
K Kokot ◽  
S Gaul ◽  
J Okun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Prolonged Treatment ◽  
Marker Genes ◽  
Human Endothelial Cells ◽  
Mesenchymal Transition ◽  
Mediated Effects ◽  
Funding Sources ◽  
Potential Impact ◽  
Endothelial To Mesenchymal Transition

Abstract Background and purpose Trimethylamine N-oxide (TMAO) is associated with a higher risk of atherosclerotic diseases. However, the underlying molecular mechanisms are not completely understood. Inflammation and following endothelial-to-mesenchymal transition (EndMT) – a process where endothelial cells (ECs) lose their function and phenotype and gain a mesenchymal character – contribute to the development of atherosclerosis. We therefore aimed to investigate the potential uptake of TMAO into ECs and its potential impact on inflammation and subsequent EndMT. Methods and results Tandem mass spectrometry revealed a time-dependent uptake of TMAO into primary human endothelial cells of 0.5 nmol/mg protein within the first 30 minutes and of 5.8 nmol/mg within 24 hours. The uptake of TMAO resulted in a significant increase of inflammation as measured by E-selectin expression (+63.8-fold). A prolonged treatment with TMAO for 3 days resulted in an increase of EndMT indicated by a significant increase of the mesenchymal marker genes Versican (+6.8-fold) and Calponin (+11.9-fold), as well as a concomitant decrease of the endothelial marker LYVE1 (−92%). For identification of a potential TMAO transporter in human endothelial cells, we screened for the expression of Solute Carrier Family member transporters in ECs. Through our research, overexpression of the carrier A5 in ECs resulted in a 36% higher intracellular TMAO concentration as early as 30 minutes. In turn, causing a knockdown of A5 prevented TMAO induced inflammation (−77.8% induction of E-Selectin) and EndMT (−98,3% induction of Versican and −461% induction of Calponin). Conclusion Using a large screening approach, we identified A5 as the first TMAO transporter described in ECs. TMAO uptake results in increased inflammation of ECs and induction of EndMT. The data identify a novel mechanism of TMAO uptake into human ECs that may help to better understand lifestyle-mediated effects on atherosclerosis. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

2019 ◽  
Vol 20 (3) ◽  
pp. 458 ◽  
Author(s):  
Fernanda Ursoli Ferreira ◽  
Lucas Eduardo Botelho Souza ◽  
Carolina Hassibe Thomé ◽  
Mariana Tomazini Pinto ◽  
Clarice Origassa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Umbilical Vein ◽  
Transforming Growth Factor Β ◽  
Selective Inhibition ◽  
Mesenchymal Transition ◽  
Best Response ◽  
Endothelial To Mesenchymal Transition

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and tumor progression. The signaling pathway of the transforming growth factor β (TGF-β) is an important molecular route responsible for EndMT activation. However, it is unclear whether the anatomic location of endothelial cells influences the activation of molecular pathways responsible for EndMT induction. Our study investigated the molecular mechanisms and signaling pathways involved in EndMT induced by TGF-β2 in macrovascular ECs obtained from different sources. For this purpose, we used four types of endothelial cells (coronary artery endothelial cells, CAECs; primary aortic endothelial cells PAECs; human umbilical vein endothelia cells, HUVECs; and human pulmonary artery endothelial cells, HPAECs) and stimulated with 10 ng/mL of TGF-β2. We observed that among the ECs analyzed in this study, PAECs showed the best response to the TGF-β2 treatment, displaying phenotypic changes such as loss of endothelial marker and acquisition of mesenchymal markers, which are consistent with the EndMT activation. Moreover, the PAECs phenotypic transition was probably triggered by the extracellular signal–regulated kinases 1/2 (ERK1/2) signaling pathway activation. Therefore, the anatomical origin of ECs influences their ability to undergo EndMT and the selective inhibition of the ERK pathway may suppress or reverse the progression of diseases caused or aggravated by the involvement EndMT activation.

Biliverdin reductase deficiency triggers an endothelial-to-mesenchymal transition in human endothelial cells

2019 ◽  
Vol 678 ◽  
pp. 108182
Author(s):  
Damian Klóska ◽  
Aleksandra Kopacz ◽  
Aleksandra Piechota-Polańczyk ◽  
Christoph Neumayer ◽  
Ihor Huk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Endothelial Cells ◽  
Biliverdin Reductase ◽  
Mesenchymal Transition ◽  
Reductase Deficiency ◽  
Endothelial To Mesenchymal Transition

scholarly journals MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease

2021 ◽  
Author(s):  
João P. Monteiro ◽  
Julie Rodor ◽  
Axelle Caudrillier ◽  
Jessica P Scanlon ◽  
Ana-Mishel Spiroski ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Molecular Mechanisms ◽  
Clinical Samples ◽  
Vascular Remodelling ◽  
Mesenchymal Transition ◽  
Polypyrimidine Tract Binding Protein ◽  
Endothelial To Mesenchymal Transition

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodelling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long non-coding RNAs (lncRNAs). Objective: To investigate the role of lncRNAs in EndMT and their relevance to vascular remodelling. Methods and Results: To study EndMT in vitro, primary endothelial cells (EC) were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-sequencing were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human EC types undergoing EndMT in vitro. MIR503HG depletion induced a spontaneous EndMT phenotype, while its overexpression repressed hallmark EndMT changes, regulating 29% of its transcriptome signature. Importantly, the phenotypic changes induced by MIR503HG were independent of miR-424 and miR-503, which overlap the lncRNA locus. The pathological relevance of MIR503HG down-regulation was confirmed in vivo using Sugen/Hypoxia (SuHx)-induced pulmonary hypertension (PH) in mouse, as well as in human clinical samples, in lung sections and blood outgrowth endothelial cells (BOECs) from pulmonary arterial hypertension (PAH) patients. Overexpression of human MIR503HG in SuHx mice led to reduced mesenchymal marker expression, suggesting MIR503HG therapeutic potential. We also revealed that MIR503HG interacts with the Polypyrimidine Tract Binding Protein 1 (PTB1) and regulates its protein level. PTBP1 regulation of EndMT markers suggests that the role of MIR503HG in EndMT might be mediated in part by PTBP1. Conclusions: This study reports a novel lncRNA transcriptional profile associated with EndMT and reveals the crucial role of the loss of MIR503HG in EndMT and its relevance to pulmonary hypertension.

scholarly journals New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 610
Author(s):  
Eloisa Romano ◽  
Irene Rosa ◽  
Bianca Saveria Fioretto ◽  
Marco Matucci-Cerinic ◽  
Mirko Manetti
Keyword(s):  
Endothelial Cells ◽  
Systemic Sclerosis ◽  
Vessel Wall ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Wall ◽  
Vascular Lesions ◽  
Tissue Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.

scholarly journals Epithelial Wntless (Wls) regulates postnatal alveologenesis

Development ◽  
2021 ◽  
Author(s):  
Yinshan Fang ◽  
Hongxia Shao ◽  
Qi Wu ◽  
Neng Chun Wong ◽  
Natalie Tsong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gas Exchange ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Alveolar Epithelium ◽  
Mesenchymal Cells ◽  
Collagen Deposition ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Alveolar Formation

Alveologenesis requires the coordinated modulation of the epithelial and mesenchymal compartments to generate mature alveolar saccules for efficient gas exchange. However, the molecular mechanisms underlying the epithelial-mesenchymal interaction during alveologenesis are poorly understood. Here, we report that Wnts produced by epithelial cells are critical for neonatal alveologenesis. Deletion of the Wnt chaperon protein Wntless homolog (Wls) disrupts alveolar formation, resulting in enlarged saccules in Sftpc-Cre/Nkx2.1-Cre; Wlsloxp/loxp mutants. Although commitment of the alveolar epithelium is unaffected, α-SMA+ mesenchymal cells persist in the alveoli accompanied by increased collagen deposition and mutants exhibit exacerbated fibrosis following bleomycin challenge. Notably, α-SMA+ cells include a significant number of endothelial cells resembling endothelial to mesenchymal transition (EndMT) which is also present in Ager-CreER; Wlsloxp/loxp mutants following early postnatal Wls deletion. These findings provide initial evidence that epithelial-derived Wnts are critical for the differentiation of the surrounding mesenchyme during early postnatal alveologenesis.

scholarly journals Atheroprone flow enhances the endothelial-to-mesenchymal transition

2018 ◽  
Vol 315 (5) ◽  
pp. H1293-H1303 ◽  
Author(s):  
Baochang Lai ◽  
Zhao Li ◽  
Ming He ◽  
Yili Wang ◽  
Lili Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Rna Sequencing ◽  
Sirtuin 1 ◽  
Marker Genes ◽  
Sequencing Data ◽  
Mesenchymal Transition ◽  
A Genome ◽  
Endothelial To Mesenchymal Transition

The endothelial-to-mesenchymal transition (EndoMT) is a cellular process featuring decreased expression of endothelial marker genes but increased expression of mesenchymal marker genes. The EndoMT is involved in endothelial dysfunction and the pathogenesis of atherosclerosis. To investigate the dynamic expression of EndoMT genes in vascular endothelial cells under atheroprotective pulsatile shear stress (PS) and atheroprone oscillatory shear stress (OS), we analyzed RNA sequencing data from multitimepoint shear-stress experiments. This unbiased analysis involving next-generation sequencing confirmed that PS and OS had an opposite effect in regulating EndoMT genes. Further experimental validations with H2O2 and gain- and loss-of-function approaches indicated that reactive oxygen species are involved in OS-induced EndoMT, whereas AMP-activated protein kinase and sirtuin-1 could inhibit OS-induced EndoMT. Furthermore, compared with PS, OS increased the DNA methylation of the promoter regions of von Willebrand factor, CD31, and cadherin 5 genes but decreased that of cadherin 2, fibroblast-specific protein 1, and vimentin. The translational implication of the present study builds on the ability of the antidiabetic drug metformin and cholesterol-lowering drug atorvastatin to suppress the EndoMT in cultured endothelial cells and in mouse aortas. NEW & NOTEWORTHY Our RNA sequencing data provided a genome-wide and unbiased view of the shear stress regulation of the endothelial-to-mesenchymal transition (EndoMT) in the endothelium. Furthermore, epigenetic regulation (e.g., DNA methylation) is a key mechanism involved in shear stress-regulated EndoMT. The translational implication of this study is that cardiovascular medications such as statins and metformin have similar beneficial effects as that of atheroprotective flow by mitigating EndoMT.

scholarly journals Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

2016 ◽  
Vol 310 (11) ◽  
pp. L1185-L1198 ◽  
Author(s):  
Toshio Suzuki ◽  
Yuji Tada ◽  
Rintaro Nishimura ◽  
Takeshi Kawasaki ◽  
Ayumi Sekine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Endothelial Cells ◽  
Repair Process ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Oxidase Inhibition ◽  
Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

scholarly journals LncRNA AERRIE Is Required for Sulfatase 1 Expression, but Not for Endothelial-to-Mesenchymal Transition

2021 ◽  
Vol 22 (15) ◽  
pp. 8088
Author(s):  
Tan Phát Pham ◽  
Anke S. van Bergen ◽  
Veerle Kremer ◽  
Simone F. Glaser ◽  
Stefanie Dimmeler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Transcription Factors ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Inflammatory Signals ◽  
Pathological Conditions ◽  
Non Coding Rna ◽  
Endothelial To Mesenchymal Transition ◽  
Long Non Coding Rna

Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated.

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