scholarly journals The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
C. Peghaire ◽  
N. P. Dufton ◽  
M. Lang ◽  
I. I. Salles-Crawley ◽  
J. Ahnström ◽  
...  
Keyword(s):  
Shear Stress ◽  
Transcription Factor ◽  
Chromatin Immunoprecipitation ◽  
Spontaneous Thrombosis ◽  
Protective Function ◽  
Low Shear Stress ◽  
Reporter Assays ◽  
Endothelial Homeostasis ◽  
Low Shear

Abstract Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS.

scholarly journals Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3563
Author(s):  
Karthika Chandran Latha ◽  
Ahalya Sreekumar ◽  
Vyshna Beena ◽  
Binil Raj S.S. ◽  
RaviKumar B. Lakkappa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Venous Insufficiency ◽  
Varicose Veins ◽  
Disturbed Flow ◽  
Mesenchymal Transition ◽  
Venous Diseases ◽  
Low Shear Stress ◽  
Low Shear

Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFβ inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins via activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.

scholarly journals Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites

2017 ◽  
Vol 37 (11) ◽  
pp. 2087-2101 ◽  
Author(s):  
Shuang Feng ◽  
Neil Bowden ◽  
Maria Fragiadaki ◽  
Celine Souilhol ◽  
Sarah Hsiao ◽  
...  
Keyword(s):  
Shear Stress ◽  
Transcription Factor ◽  
Atmospheric Oxygen ◽  
Quantitative Polymerase Chain Reaction ◽  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Hypoxia Inducible Factor 1Α ◽  
Low Shear Stress ◽  
Low Shear

Objective— Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathway to lesion initiation. Approach and Results— Quantitative polymerase chain reaction and en face staining revealed that HIF1α was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1α in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-κB that induced HIF1α transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1α protein. Gene silencing revealed that HIF1α enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1α, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1α in hypercholesterolemic apolipoprotein E–defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1α drives inflammation and vascular dysfunction at low shear stress regions. Conclusions— Mechanical low shear stress activates HIF1α at atheroprone regions of arteries via nuclear factor-κB and Cezanne. HIF1α promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.

scholarly journals Rapamycin Attenuates Endothelial Apoptosis Induced by Low Shear Stress via mTOR and Sestrin1 Related Redox Regulation

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Junxia Zhang ◽  
Zhimei Wang ◽  
Junjie Zhang ◽  
Guangfeng Zuo ◽  
Bing Li ◽  
...  
Keyword(s):  
Shear Stress ◽  
Redox Regulation ◽  
Mammalian Target Of Rapamycin ◽  
Flow Chamber ◽  
Parallel Plate Flow Chamber ◽  
Low Shear Stress ◽  
Interfering Rna ◽  
Low Shear

Background. Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation.Methods and Results. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not.Conclusions. Rapamycin may prohibit sestrin1 downregulation through targeting mTORC2 in appeasing LSS induced EC oxidative apoptosis. Our results provide thein vitroevidence to explain the pathophysiology of RES stented arteries.

Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2

2021 ◽  
Vol 545 ◽  
pp. 20-26
Author(s):  
AFang Li ◽  
LiLan Tan ◽  
ShuLei Zhang ◽  
Jun Tao ◽  
Zuo Wang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Down Regulation ◽  
Low Shear Stress ◽  
Mesenchymal Transformation ◽  
Low Shear

Plaque and Shear Stress Distribution in Human Coronary Bifurcations: a Multi-Slice Computed Tomography Study

2007 ◽  
Author(s):  
Alina G. van der Giessen ◽  
Jolanda J. Wentzel ◽  
Frans N. van de Vosse ◽  
Antonius F. van der Steen ◽  
Pim J. de Feyter ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Shear Stress ◽  
Outer Wall ◽  
Atherosclerotic Plaques ◽  
Advanced Stage ◽  
Flow Divider ◽  
Low Shear Stress ◽  
Curved Vessels ◽  
Early Atherosclerosis ◽  
Low Shear

It is generally accepted that early atherosclerosis develops in low shear-stress (SS) regions such as the outer wall of arterial bifurcations and the inner bend of curved vessels (1). However, in clinical practice, it is common to observe atherosclerotic plaques at the flow-divider, or carina, of coronary bifurcations (2). Plaques at the carina are more frequently found in symptomatic patients, and may represent a more advanced stage of atherosclerosis. The carina is located in a region which is exposed to high SS. We hypothesize that if plaques are located in atheroprotective high SS regions, they have grown circumferentially from the atherogenic low SS regions.

CXCR4 expression in atherosclerotic lesions induced by low shear stress

2008 ◽  
Vol 32 (3) ◽  
pp. S18-S19
Author(s):  
Dang Heng Wei ◽  
Gui Xue Wang ◽  
Yi Ping Xia ◽  
Jian Jun Lei ◽  
Lu Shang Liu ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cxcr4 Expression ◽  
Atherosclerotic Lesions ◽  
Low Shear Stress ◽  
Low Shear

scholarly journals Low Shear Stress Induced HMGB1 Translocation and Release via PECAM-1/PARP-1 Pathway to Induce Inflammation Response

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120586 ◽  
Author(s):  
Wei-dong Qin ◽  
Shao-hua Mi ◽  
Chen Li ◽  
Gui-xia Wang ◽  
Jian-ning Zhang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Inflammation Response ◽  
Low Shear Stress ◽  
Parp 1 ◽  
Low Shear
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