scholarly journals Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway

2021 ◽  
Vol 7 (28) ◽  
pp. eabg5060
Author(s):  
Vedanta Mehta ◽  
Kar-Lai Pang ◽  
Christopher S. Givens ◽  
Zhongming Chen ◽  
Jianhua Huang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Disease ◽  
Mechanical Forces ◽  
Vascular Health ◽  
Cell Plasticity ◽  
Critical Determinant ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Genetic Targeting

The response of endothelial cells to mechanical forces is a critical determinant of vascular health. Vascular pathologies, such as atherosclerosis, characterized by abnormal mechanical forces are frequently accompanied by endothelial-to-mesenchymal transition (EndMT). However, how forces affect the mechanotransduction pathways controlling cellular plasticity, inflammation, and, ultimately, vessel pathology is poorly understood. Here, we identify a mechanoreceptor that is sui generis for EndMT and unveil a molecular Alk5-Shc pathway that leads to EndMT and atherosclerosis. Depletion of Alk5 abrogates shear stress–induced EndMT responses, and genetic targeting of endothelial Shc reduces EndMT and atherosclerosis in areas of disturbed flow. Tensional force and reconstitution experiments reveal a mechanosensory function for Alk5 in EndMT signaling that is unique and independent of other mechanosensors. Our findings are of fundamental importance for understanding how mechanical forces regulate biochemical signaling, cell plasticity, and vascular disease.

scholarly journals Endothelial Plasticity: Shifting Phenotypes through Force Feedback

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Guido Krenning ◽  
Valerio G. Barauna ◽  
José E. Krieger ◽  
Martin C. Harmsen ◽  
Jan-Renier A. J. Moonen
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Force Feedback ◽  
Fluid Shear Stress ◽  
Cyclic Strain ◽  
Endothelial Lining ◽  
Mesenchymal Transition ◽  
Hemodynamic Forces ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Plasticity

The endothelial lining of the vasculature is exposed to a large variety of biochemical and hemodynamic stimuli with different gradients throughout the vascular network. Adequate adaptation requires endothelial cells to be highly plastic, which is reflected by the remarkable heterogeneity of endothelial cells in tissues and organs. Hemodynamic forces such as fluid shear stress and cyclic strain are strong modulators of the endothelial phenotype and function. Although endothelial plasticity is essential during development and adult physiology, proatherogenic stimuli can induce adverse plasticity which contributes to disease. Endothelial-to-mesenchymal transition (EndMT), the hallmark of endothelial plasticity, was long thought to be restricted to embryonic development but has emerged as a pathologic process in a plethora of diseases. In this perspective we argue how shear stress and cyclic strain can modulate EndMT and discuss how this is reflected in atherosclerosis and pulmonary arterial hypertension.

scholarly journals Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress

2015 ◽  
Vol 108 (3) ◽  
pp. 377-386 ◽  
Author(s):  
Jan-Renier A.J. Moonen ◽  
Ee Soo Lee ◽  
Marc Schmidt ◽  
Monika Maleszewska ◽  
Jasper A. Koerts ◽  
...  
Keyword(s):  
Shear Stress ◽  
Vascular Disease ◽  
Fluid Shear Stress ◽  
Fluid Shear ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Proliferative Vascular Disease

scholarly journals Single-cell epigenomic tracing of lifelong endothelial cell plasticity across mouse organs

2021 ◽  
Author(s):  
Xianhong Yu ◽  
Yaxi Liu ◽  
Xiaoge Liu ◽  
Haiqing Xiong ◽  
Aibin He
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Endothelial Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Developmental Origins ◽  
Cellular Plasticity ◽  
Cell Plasticity ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Endothelial cells (ECs) across ages and tissues are highly heterogeneous in developmental origins, structures, functions, and cellular plasticity. Here, we applied CoBATCH for single-cell epigenomic tracing of dynamic EC lineage histories in five mouse organs from development to ageing. Our analyses showed that epigenomic memory reflects both developmental origins and tissue-restricted specialization of EC sublineages but with varying time lengths across organs. To gain insights into cellular plasticity of ECs, we identified bivalent chromatin occupancy of otherwise mutually exclusive EC- (ERG) and mesenchymal-specific (TWIST1/SNAI1) transcription factors promoting endothelial-to-mesenchymal transition. We further revealed that pseudotime trajectories by histone modifications H3K36me3 and H3K27ac faithfully recapitulate short- and long-range EC fate change over senescence, respectively. Together, our data provide a unique exploration of chromatin-level cell fate regulation of organotypic EC lineages across the lifespan.

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.

scholarly journals Mapping the endothelial cell S-Sulfhydrome highlights the crucial role of integrin sulfhydration in vascular function

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
D R Bibli ◽  
D R Hu ◽  
D R Looso ◽  
D R Weigert ◽  
D R Wittig ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Vascular Disease ◽  
Disulfide Bond ◽  
Mesenteric Arteries ◽  
Human Endothelial Cells ◽  
Β3 Integrin ◽  
Static Conditions ◽  
Protein Disulfide

Abstract Background In vascular endothelial cells, cysteine metabolism by the cystathionine-γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (H2Sn), that exert their biological actions via cysteine S-sulfhydration of target proteins. This study set out to map the “S-sulfhydrome” i.e. the spectrum of proteins targeted by H2Sn in human endothelial cells. Methods LC-MS/MS was used to identify S-sulfhydrated cysteines in endothelial cell proteins and β3 integrin intra-protein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements and flow-induced vasodilatation in endothelial cell-specific CSE knock out mice and a small collective of patients with endothelial dysfunction. Results Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low), (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression, and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing H2Sn donor, SG1002. The endothelial cell “S-sulfhydrome” consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on β3 integrin in detail we found that S-sulfhydration affected intra-protein disulfide bond formation and was required for the maintenance of an extended-open conformation of the β leg. β3 integrin S-sulfhydration was required for endothelial cell mechanotransduction in vitro as well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of S-sulfhydration impaired interactions between β3 integrin and Gα13, resulting in the constitutive activation of RhoA and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low H2Sn generation, impaired flow-induced dilatation and a failure to detect β3 integrin S-sulfhydration, all of which were rescued following the administration of an H2S supplement. Conclusions Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short term H2Sn supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

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