scholarly journals Requisite Role for Nck Adaptors in Cardiovascular Development, Endothelial-to-Mesenchymal Transition, and Directed Cell Migration

2015 ◽  
Vol 35 (9) ◽  
pp. 1573-1587 ◽  
Author(s):  
Derek L. Clouthier ◽  
Cameron N. Harris ◽  
Richard A. Harris ◽  
Claire E. Martin ◽  
Mira C. Puri ◽  
...  
Keyword(s):  
Cell Types ◽  
Actin Dynamics ◽  
Cardiovascular Development ◽  
Vascular Networks ◽  
Mesenchymal Transition ◽  
Perivascular Cell ◽  
Cytoskeleton Organization ◽  
Directed Cell Migration ◽  
Actin Cytoskeleton Organization ◽  
Endothelial To Mesenchymal Transition

Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development.

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 Curcumin Blunts IL-6 Dependent Endothelial‐to‐Mesenchymal Transition to Alleviate Renal Allograft Fibrosis Through Autophagy Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiajun Zhou ◽  
Mengtian Yao ◽  
Minghui Zhu ◽  
Mengchao Li ◽  
Qiwei Ke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kidney Transplantation ◽  
Renal Allograft ◽  
Umbilical Vein ◽  
Rat Kidney ◽  
Graft Loss ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Fibrosis contributes to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT) plays an important role in the development of fibrosis following kidney transplantation. Autophagy plays an important role in the homeostasis of diverse cell types including endothelial cells. Here we demonstrate that inhibition of autophagy by treatment with 3-methyladenine (3-MA) or by silencing autophagy-related (ATG)5 promoted interleukin (IL)-6–dependent EndMT in human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs), and autophagy inactivation was associated with EndMT in patients with chronic allograft dysfunction. IL-6 level was significantly higher in the culture medium of HUVECs transfected with ATG5 siRNA or treated with 3-MA compared to the respective control groups. IL-6 application induced EndMT in HUVECs and HRGECs, whereas antibody-mediated neutralization of IL-6 suppressed EndMT induced by ATG5 silencing. The protective role of curcumin (Cur) against allograft fibrosis was confirmed in a rat kidney transplantation model of F344 donors to Lewis recipients. Curcumin—a natural polyphenol compound with known antifibrotic effects in various tissues—alleviated IL-6–induced EndMT and promoted autophagy in the allografted organ and in HUVECs. This is the first demonstration of the role of autophagy in renal allograft fibrosis; our findings indicate that curcumin can alleviate chronic renal allograft injury by suppressing IL-6–dependent EndMT via activation of autophagy.

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 The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Ankur Balmik ◽  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Protein Misfolding ◽  
Tau Phosphorylation ◽  
Actin Dynamics ◽  
Histone Deacetylase 6 ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization ◽  
Aggresome Formation ◽  
Gsk 3Β ◽  
Misfolding Diseases

Abstract Background Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein. Methods Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization. Results HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level. Conclusions HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases.

scholarly journals MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis

2021 ◽  
Vol 22 (16) ◽  
pp. 8629
Author(s):  
Nina P. Jordan ◽  
Samuel J. Tingle ◽  
Victoria G. Shuttleworth ◽  
Katie Cooke ◽  
Rachael E. Redgrave ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Heart Tissue ◽  
Lineage Tracing ◽  
Ischaemic Injury ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Over Expression ◽  
Endothelial To Mesenchymal Transition

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.

scholarly journals SH2-Containing Inositol 5′-Phosphatase SHIP2 Associates with the p130Cas Adapter Protein and Regulates Cellular Adhesion and Spreading

2001 ◽  
Vol 21 (4) ◽  
pp. 1416-1428 ◽  
Author(s):  
Nagendra Prasad ◽  
Robert S. Topping ◽  
Stuart J. Decker
Keyword(s):  
Catalytic Domain ◽  
Protein A ◽  
Cell Types ◽  
Cellular Adhesion ◽  
Sh2 Domain ◽  
Adapter Protein ◽  
Cytoskeleton Organization ◽  
Phosphorylated Form ◽  
Immunofluorescence Studies ◽  
Actin Cytoskeleton Organization

ABSTRACT In a previous study, we found that the SHIP2 protein became tyrosine phosphorylated and associated with the Shc adapter protein in response to the treatment of cells with growth factors and insulin (T. Habib, J. A. Hejna, R. E. Moses, and S. J. Decker, J. Biol. Chem. 273:18605–18609, 1998). We describe here a novel interaction between SHIP2 and the p130Cas adapter protein, a mediator of actin cytoskeleton organization. SHIP2 and p130Cas association was detected in anti-SHIP2 immunoprecipitates from several cell types. Reattachment of trypsinized cells stimulated tyrosine phosphorylation of SHIP2 and increased the formation of a complex containing SHIP2 and a faster-migrating tyrosine-phosphorylated form of p130Cas. The faster-migrating form of p130Cas was no longer recognized by antibodies to the amino terminus of p130Cas and appeared to be generated through proteolysis. Interaction of the SHIP2 protein with the various forms of p130Cas was mediated primarily through the SH2 domain of SHIP2. Immunofluorescence studies indicated that SHIP2 localized to focal contacts and to lamellipodia. Increased adhesion was observed in HeLa cells transiently expressing exogenous WT-SHIP2. These effects were not seen with SHIP2 possessing a mutation in the SH2 domain (R47G). Transfection of a catalytic domain deletion mutant of SHIP2 (ΔRV) inhibited cell spreading. Taken together, our studies suggest an important role for SHIP2 in adhesion and spreading.

scholarly journals The MAP Kinase Slt2 Is Involved in Vacuolar Function and Actin Remodeling in Saccharomyces cerevisiae Mutants Affected by Endogenous Oxidative Stress

2013 ◽  
Vol 79 (20) ◽  
pp. 6459-6471 ◽  
Author(s):  
Nuria Pujol-Carrion ◽  
Mima I. Petkova ◽  
Luis Serrano ◽  
Maria Angeles de la Torre-Ruiz
Keyword(s):  
Oxidative Stress ◽  
Actin Cytoskeleton ◽  
Iron Homeostasis ◽  
Synthetic Lethality ◽  
Actin Dynamics ◽  
Triple Mutant ◽  
Cytoskeleton Organization ◽  
Cellular Models ◽  
Vacuole Fusion ◽  
Actin Cytoskeleton Organization

ABSTRACTOxidative stress causes transient actin cytoskeleton depolarization and also provokes vacuole fragmentation in wild-type cells. Under conditions of oxidative stress induced by hydrogen peroxide, the Slt2 protein is required to repolarize the actin cytoskeleton and to promote vacuole fusion. In this study, we show thatgrx3 grx4andgrx5mutants are cellular models of endogenous oxidative stress. This stress is the result of alterations in iron homeostasis that lead to impairment of vacuolar function and also to disorganization of the actin cytoskeleton. Slt2 overexpression suppresses defects in vacuolar function and actin cytoskeleton organization in thegrx3 grx4mutant. Slt2 exerts this effect independently of the intracellular levels of reactive oxygen species (ROS) and of iron homeostasis. The deletion ofSLT2in thegrx3 grx4mutant results in synthetic lethality related to vacuolar function with substantial vacuole fragmentation. The observation that both Vps4 and Vps73 (two proteins related to vacuole sorting) suppress vacuole fragmentation and actin depolarization in thegrx3 grx4 slt2triple mutant strengthens the hypothesis that Slt2 plays a role in vacuole homeostasis related to actin dynamics. Here we show that insod1,grx5, andgrx3 grx4 slt2mutants, all of which are affected by chronic oxidative stress, the overexpression of Slt2 favors vacuole fusion through a mechanism dependent on an active actin cytoskeleton.

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

2020 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
Vanessa Núñez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

ABSTRACTMacrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

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.

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