Endothelial-to-Mesenchymal Transition: Role in Cardiac Fibrosis

2020 ◽  
Vol 26 (1) ◽  
pp. 3-11
Author(s):  
Weijia Cheng ◽  
Xiao Li ◽  
Dongling Liu ◽  
Chaochu Cui ◽  
Xianwei Wang
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Fibrosis ◽  
Mesenchymal Cell ◽  
Therapeutic Interventions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Pathological Conditions ◽  
Complex Biological Process ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process by which endothelial cells lose their endothelial cell characteristics and acquire mesenchymal cell properties under certain physiological or pathological conditions. Recently, it has been found that EndMT plays an important role in the occurrence and development of fibrotic cardiovascular diseases. In this review, we first summarize the main induction pathways involved in EndMT process. In addition, we discuss the role of EndMT in fibrotic cardiovascular diseases and its potential implication in new therapeutic interventions.

scholarly journals Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Valentin Platel ◽  
Sébastien Faure ◽  
Isabelle Corre ◽  
Nicolas Clere
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Therapy Resistance ◽  
Experimental Conditions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Cancer cells evolve in a very complex tumor microenvironment, composed of several cell types, among which the endothelial cells are the major actors of the tumor angiogenesis. Today, these cells are also characterized for their plasticity, as endothelial cells have demonstrated their potential to modify their phenotype to differentiate into mesenchymal cells through the endothelial-to-mesenchymal transition (EndoMT). This cellular plasticity is mediated by various stimuli including transforming growth factor-β (TGF-β) and is modulated dependently of experimental conditions. Recently, emerging evidences have shown that EndoMT is involved in the development and dissemination of cancer and also in cancer cell to escape from therapeutic treatment. In this review, we summarize current updates on EndoMT and its main induction pathways. In addition, we discuss the role of EndoMT in tumorigenesis, metastasis, and its potential implication in cancer therapy resistance.

scholarly journals Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases

2019 ◽  
Vol 99 (2) ◽  
pp. 1281-1324 ◽  
Author(s):  
Sonsoles Piera-Velazquez ◽  
Sergio A. Jimenez
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Transforming Growth Factor ◽  
Mesenchymal Cell ◽  
Human Diseases ◽  
Type I ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Complex Biological Process ◽  
Endothelial To Mesenchymal Transition

Numerous studies have demonstrated that endothelial cells are capable of undergoing endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation. EndMT is a complex biological process in which endothelial cells adopt a mesenchymal phenotype displaying typical mesenchymal cell morphology and functions, including the acquisition of cellular motility and contractile properties. Endothelial cells undergoing EndMT lose the expression of endothelial cell-specific proteins such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and initiate the expression of mesenchymal cell-specific genes and the production of their encoded proteins including α-smooth muscle actin, extra domain A fibronectin, N-cadherin, vimentin, fibroblast specific protein-1, also known as S100A4 protein, and fibrillar type I and type III collagens. Transforming growth factor-β1 is considered the main EndMT inducer. However, EndMT involves numerous molecular and signaling pathways that are triggered and modulated by multiple and often redundant mechanisms depending on the specific cellular context and on the physiological or pathological status of the cells. EndMT participates in highly important embryonic development processes, as well as in the pathogenesis of numerous genetically determined and acquired human diseases including malignant, vascular, inflammatory, and fibrotic disorders. Despite intensive investigation, many aspects of EndMT remain to be elucidated. The identification of molecules and regulatory pathways involved in EndMT and the discovery of specific EndMT inhibitors should provide novel therapeutic approaches for various human disorders mediated by EndMT.

Transcriptional regulation of endothelial-to-mesenchymal transition in cardiac fibrosis: role of myocardin-related transcription factor A and activating transcription factor 3

2017 ◽  
Vol 95 (10) ◽  
pp. 1263-1270 ◽  
Author(s):  
Vibhuti Sharma ◽  
Nilambra Dogra ◽  
Uma Nahar Saikia ◽  
Madhu Khullar
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Cardiac Fibrosis ◽  
Activating Transcription Factor 3 ◽  
Mesenchymal Transition ◽  
Related Transcription Factor ◽  
Endothelial To Mesenchymal Transition ◽  
Activating Transcription Factor ◽  
Transcription Factor 3

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor β (TGF-β) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-β in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-β ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.

scholarly journals The Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Shahrin Islam ◽  
Kristina I. Boström ◽  
Dino Di Carlo ◽  
Craig A. Simmons ◽  
Yin Tintut ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cardiovascular System ◽  
Therapeutic Interventions ◽  
Cell Phenotype ◽  
Cardiovascular Development ◽  
Mechanical Stimuli ◽  
Mesenchymal Transition ◽  
Pulsatile Pressure ◽  
Endothelial To Mesenchymal Transition

Endothelial cells (ECs) lining the cardiovascular system are subjected to a highly dynamic microenvironment resulting from pulsatile pressure and circulating blood flow. Endothelial cells are remarkably sensitive to these forces, which are transduced to activate signaling pathways to maintain endothelial homeostasis and respond to changes in the environment. Aberrations in these biomechanical stresses, however, can trigger changes in endothelial cell phenotype and function. One process involved in this cellular plasticity is endothelial-to-mesenchymal transition (EndMT). As a result of EndMT, ECs lose cell-cell adhesion, alter their cytoskeletal organization, and gain increased migratory and invasive capabilities. EndMT has long been known to occur during cardiovascular development, but there is now a growing body of evidence also implicating it in many cardiovascular diseases (CVD), often associated with alterations in the cellular mechanical environment. In this review, we highlight the emerging role of shear stress, cyclic strain, matrix stiffness, and composition associated with EndMT in CVD. We first provide an overview of EndMT and context for how ECs sense, transduce, and respond to certain mechanical stimuli. We then describe the biomechanical features of EndMT and the role of mechanically driven EndMT in CVD. Finally, we indicate areas of open investigation to further elucidate the complexity of EndMT in the cardiovascular system. Understanding the mechanistic underpinnings of the mechanobiology of EndMT in CVD can provide insight into new opportunities for identification of novel diagnostic markers and therapeutic interventions.

scholarly journals A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition

2021 ◽  
Vol 134 (15) ◽  
Author(s):  
Cecilia Savorani ◽  
Matteo Malinverno ◽  
Roberta Seccia ◽  
Claudio Maderna ◽  
Monica Giannotta ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Bmp Signaling ◽  
Early Gene ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Pathological Conditions ◽  
Candidate Target ◽  
Smad3 Phosphorylation ◽  
Endothelial To Mesenchymal Transition

ABSTRACT Endothelial-to-mesenchymal transition (EndMT) is the biological process through which endothelial cells transdifferentiate into mesenchymal cells. During embryo development, EndMT regulates endocardial cushion formation via TGFβ/BMP signaling. In adults, EndMT is mainly activated during pathological conditions. Hence, it is necessary to characterize molecular regulators cooperating with TGFβ signaling in driving EndMT, to identify potential novel therapeutic targets to treat these pathologies. Here, we studied YAP, a transcriptional co-regulator involved in several biological processes, including epithelial-to-mesenchymal transition (EMT). As EndMT is the endothelial-specific form of EMT, and YAP (herein referring to YAP1) and TGFβ signaling cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling. We demonstrate that YAP is required to trigger TGFβ-induced EndMT response, specifically contributing to SMAD3-driven EndMT early gene transcription. We provide novel evidence that YAP acts as SMAD3 transcriptional co-factor and prevents GSK3β-mediated SMAD3 phosphorylation, thus protecting SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-induced EndMT at early stages.

scholarly journals Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Sergio A. Jimenez
Keyword(s):  
Endothelial Cells ◽  
Systemic Sclerosis ◽  
Endothelial Cell ◽  
Mesenchymal Cell ◽  
Microvascular Endothelial Cell ◽  
Potential Contribution ◽  
Mesenchymal Transition ◽  
Fibrotic Process ◽  
Endothelial To Mesenchymal Transition

The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here.

scholarly journals Autophagy attenuates endothelial-to-mesenchymal transition by promoting Snail degradation in human cardiac microvascular endothelial cells

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Jin Zou ◽  
Yanhua Liu ◽  
Bingong Li ◽  
Zeqi Zheng ◽  
Xuan Ke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanism ◽  
Cardiac Fibrosis ◽  
Microvascular Endothelial Cells ◽  
Cardiovascular Development ◽  
Mesenchymal Transition ◽  
Microvascular Endothelial ◽  
Endothelial To Mesenchymal Transition ◽  
Cardiac Microvascular Endothelial Cells

Endothelial-to-mesenchymal transition (EndMT) mainly exists in cardiovascular development and disease progression, and is well known to contribute to cardiac fibrosis. Recent studies indicated that autophagy also participates in the regulation of cardiac fibrosis. However, the precise role of autophagy in cardiac fibrosis and the underlying molecular mechanism remain unclear. The present study aimed to explore the role of autophagy in EndMT, reveal the underlying molecular mechanism, and seek new therapy for cardiac fibrosis. In the present study, we found that EndMT and autophagy were induced simultaneously by hypoxia in human cardiac microvascular endothelial cells (HCMECs). Rapamycin, an autophagy enhancer, attenuated EndMT with promoting angiogenesis, while 3-methyladenine (3-MA) and chloroquine (CQ), agents that inhibit autophagy, accelerated the progression accompanied by the decrease in counts of tube formation under hypoxia conditions. Interestingly, intervening autophagy by rapamycin, 3-MA, or CQ did not affect hypoxia-induced autocrine TGFβ signaling, but changed the expression of Snail protein without alterations in the expression of Snail mRNA. Furthermore, the colocalization of LC3 and Snail indicated that autophagy might mediate Snail degradation under hypoxia conditions in HCMECs. Interaction of p62, the substrate of autophagy, with Snail by co-immunoprecipitation especially in hypoxia-incubated cells confirmed the hypothesis. In conclusion, autophagy serves as a cytoprotective mechanism against EndMT to promote angiogenesis by degrading Snail under hypoxia conditions, suggesting that autophagy targetted therapeutic strategies may be applicable for cardiac fibrosis by EndMT.

Abstract MP02: Angiotensin II Mediates Microvascular Rarefaction In Vivo and Exacerbates Endothelial-To-Mesenchymal Transition In Vitro

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Katrin Nather ◽  
Mónica Flores-Muñoz ◽  
Rhian M Touyz ◽  
Christopher M Loughrey ◽  
Stuart A Nicklin
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Cardiac fibrosis accompanies numerous cardiovascular diseases (CVD) such as hypertension and myocardial infarction and increases myocardial stiffness leading to contractile dysfunction. Recently, endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to myocardial fibrosis. EndMT describes a process by which endothelial cells transform into mesenchymal cells such as fibroblasts and has been implicated in many fibrotic diseases. Angiotensin II (AngII) plays a key role in myocardial fibrosis and has been associated with the activation of fibroblasts to myofibroblasts and an increase in myocardial collagen deposition. Here, we assessed the role of AngII in capillary loss and EndMT in vivo and in vitro . C57BL/6J mice were infused with H 2 O (control) or 24μg/kg/hr AngII for 4 weeks. Mice infused with AngII developed significant cardiac fibrosis characterised by the deposition of collagen I (2.5-fold vs. control; p<0.05) and III (1.9-fold vs. control; p<0.05). Capillary density was assessed by CD31 immunohistochemistry and revealed significant vascular rarefaction (control 2161±111 vs . AngII 838±132 capillaries/mm 2 ; p<0.05). To investigate whether AngII can induce EndMT in vitro , human coronary artery endothelial cells were stimulated with 10ng/mL TGFβ 1 alone or in combination with 1μM AngII for 10 days. AngII significantly enhanced TGFβ 1 -induced gene expression of α-smooth muscle actin (TGFβ 1 1.8-fold; TGFβ 1 ±AngII 4.3-fold vs . control; p<0.05) and collagen I (TGFβ 1 9.2-fold; TGFβ 1 +AngII 30.2-fold vs . control; p<0.05). Concomitantly, AngII significantly increased α-smooth muscle actin protein expression (TGFβ 1 3.9-fold; TGFβ 1 +AngII 23.6-fold vs . control; p<0.05) and significantly decreased CD31 expression (TGFβ 1 0.9-fold; TGFβ 1 +AngII 0.7-fold vs . control; p<0.05), suggesting AngII acts in concert with TGFβ 1 to enhance conversion of endothelial cells to myofibroblasts. Further studies investigating the underlying mechanism, including the role of the Smad pathway, are ongoing. These results demonstrate that AngII induces vascular rarefaction in vivo and potentiates TGFβ 1 -induced EndMT in vitro. Understanding the molecular basis for these observations may help to identify new therapeutic options in CVD.

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.

scholarly journals P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Junteng Zhou ◽  
Zhichao Zhou ◽  
Xiaojing Liu ◽  
Hai-Yan Yin ◽  
Yong Tang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
P2x7 Receptor ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Experimental Studies ◽  
Therapeutic Interventions ◽  
Receptor Protein ◽  
Inflammasome Activation

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

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