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.

Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis

1992 ◽  
Vol 262 (6) ◽  
pp. C1411-C1417 ◽  
Author(s):  
R. V. Geiger ◽  
B. C. Berk ◽  
R. W. Alexander ◽  
R. M. Nerem
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Fluid Shear Stress ◽  
Temporal Analysis ◽  
Glass Capillary ◽  
Aortic Smooth Muscle ◽  
Hemodynamic Forces ◽  
Spatial And Temporal Analysis ◽  
Short And Long Term

Endothelial cells (EC) are uniquely situated to respond to hemodynamic forces. Because flow-mediated release of endothelial-derived relaxing factors is associated with increased EC intracellular calcium ([Ca2+]i), we sought to determine the effects of fluid shear stress on EC [Ca2+]i. Cells were subjected to flow in parallel-plate flow chambers and glass capillary tubes, and single cell [Ca2+]i was measured using fura-2. Upon initiation of flow (shear stress of 30 dyn/cm2), [Ca2+]i increased within 30 s to a peak value (approximately 4 times basal) and then decreased slowly to a plateau (approximately 2 times basal) that persisted for greater than 5 min. A striking finding was that the increases in [Ca2+]i were nonhomogeneous; the nuclear region and a periplasma membrane region were higher than the cytosol. After flow cessation, the increase in [Ca2+]i could be elicited repeatedly by resumption of flow. Removing extracellular Ca2+ did not eliminate the response. In contrast to EC, rat aortic smooth muscle cells showed no flow-mediated increase in [Ca2+]i. The complexity of EC [Ca2+]i response to flow suggests regulation of [Ca2+]i by several mechanisms that may serve a role in both short- and long-term EC responses to flow.

scholarly journals Macrorheology and adaptive microrheology of endothelial cells subjected to fluid shear stress

2007 ◽  
Vol 293 (5) ◽  
pp. C1568-C1575 ◽  
Author(s):  
Jhanvi H. Dangaria ◽  
Peter J. Butler
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Fluid Shear Stress ◽  
Vascular Endothelial Cells ◽  
Step Change ◽  
Time Dependent ◽  
Creep Function ◽  
Fluid Shear ◽  
Hemodynamic Forces ◽  
Forcing Function

Vascular endothelial cells (ECs) respond to temporal and spatial characteristics of hemodynamic forces by alterations in their adhesiveness to leukocytes, secretion of vasodilators, and permeability to blood-borne constituents. These physiological and pathophysiological changes are tied to adaptation of cell mechanics and mechanotransduction, the process by which cells convert forces to intracellular biochemical signals. The exact time scales of these mechanical adaptations, however, remain unknown. We used particle-tracking microrheology to study adaptive changes in intracellular mechanics in response to a step change in fluid shear stress, which simulates both rapid temporal and steady features of hemodynamic forces. Results indicate that ECs become significantly more compliant as early as 30 s after a step change in shear stress from 0 to 10 dyn/cm2followed by recovery of viscoelastic parameters within 4 min of shearing, even though shear stress was maintained. After ECs were sheared for 5 min, return of shear stress to 0 dyn/cm2in a stepwise manner did not result in any further rheological adaptation. Average vesicle displacements were used to determine time-dependent cell deformation and macrorheological parameters by fitting creep function to a linear viscoelastic liquid model. Characteristic time and magnitude for shear-induced deformation were 3 s and 50 nm, respectively. We conclude that ECs rapidly adapt their mechanical properties in response to shear stress, and we provide the first macrorheological parameters for time-dependent deformations of ECs to a physiological forcing function. Such studies provide insight into pathologies such as atherosclerosis, which may find their origins in EC mechanics.

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-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 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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