Phosphodiesterase 4D7 (PDE4D7) Selectively Regulates cAMP-mediated Control of Human Arterial Endothelial Cell Transcriptomic Responses to Fluid Shear Stress

2020 ◽  
Author(s):  
Jonah Burke-Kleinman ◽  
Donald Maurice
Keyword(s):  
Shear Stress ◽  
Fluid Shear Stress ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Transcriptional Responses ◽  
Arterial Endothelial Cell ◽  
Frictional Forces ◽  
Prevention Of Atherosclerosis ◽  
In Cells

Human arterial endothelial cells (HAECs) regulate their phenotype by integrating signals encoded in the frictional forces exerted by flowing blood, fluid shear stress (FSS). High laminar FSS promotes establishment of adaptive HAEC phenotype protective against atherosclerosis, whereas low or disturbed FSS cause HAECs to adopt athero-prone phenotypes. A vascular endothelial cadherin (VE cadherin)-based mechanosensory complex allows HAECs to regulate barrier function, cell morphology and gene expression in response to FSS. Previously, we reported that this mechanosensor integrated exchange protein activated by cAMP (EPAC1) and a PDE4D gene derived cyclic nucleotide phosphodiesterase (PDE), but had not identified the PDE4D variant involved. Our hypothesis here was that only one of the two ~100 kDa PDE4D variants expressed in HAECs coordinated these responses. Now, we show one unique PDE4D splice variant, PDE4D7, controls transcriptional responses of HAECs to FSS while another, PDE4D5, does not. Adaptive transcriptional responses of HAECs subjected to laminar FSS in vitro were blunted in cells in which PDE4D7 was silenced, but unaffected in cells with silenced PDE4D5. This work identifies a specific therapeutic target for the treatment or prevention of atherosclerosis and improves our understanding of the role of cAMP-signaling in modulating mechanosensory signal transduction in the vascular endothelium.

scholarly journals Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro.

1986 ◽  
Vol 83 (7) ◽  
pp. 2114-2117 ◽  
Author(s):  
P. F. Davies ◽  
A. Remuzzi ◽  
E. J. Gordon ◽  
C. F. Dewey ◽  
M. A. Gimbrone
Keyword(s):  
Shear Stress ◽  
Endothelial Cell ◽  
Fluid Shear Stress ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Cell Turnover ◽  
Fluid Shear ◽  
Turbulent Fluid

scholarly journals ShearFAST: a user-friendly in vitro toolset for high throughput, inexpensive fluid shear stress experiments.

2020 ◽  
Author(s):  
Thomas Brendan Smith ◽  
Alessandro Marco De Nunzio ◽  
Kamlesh Patel ◽  
Haydn Munford ◽  
Tabeer Alam ◽  
...  
Keyword(s):  
Shear Stress ◽  
High Throughput ◽  
Fluid Shear Stress ◽  
Tracking System ◽  
Frequency Measurement ◽  
Camera Motion ◽  
Fluid Shear ◽  
Mean Frequency

Fluid shear stress is a key modulator of cellular physiology in vitro and in vivo, but its effects are under-investigated due to requirements for complicated induction methods. Herein we report the validation of ShearFAST; a smartphone application that measures the rocking profile on a standard laboratory cell rocker and calculates the resulting shear stress arising in tissue culture plates. The accuracy with which this novel approach measured rocking profiles was validated against a graphical analysis, and also against measures reported by an 8-camera motion tracking system. ShearFASTs angle assessments correlated well with both analyses (r ≥0.99, p ≤0.001) with no significant differences in pitch detected across the range of rocking angles tested. Rocking frequency assessment by ShearFAST also correlated well when compared to the two independent validatory techniques (r ≥0.99, p ≤0.0001), with excellent reproducibility between ShearFAST and video analysis (mean frequency measurement difference of 0.006 ± 0.005Hz) and motion capture analysis (mean frequency measurement difference of 0.008 ± 0.012Hz). These data make the ShearFAST assisted cell rocker model make it an attractive approach for economical, high throughput fluid shear stress experiments. Proof of concept data presented reveals a protective effect of low-level shear stress on renal proximal tubule cells submitted to simulations of pretransplant storage.

scholarly journals Lepasnya Sel Endotel Dan Vascular Endothelial Cadherin (Ve-Cadherin) Pada Huvecs Dengan Glukosa Tinggi Dan Fluid Shear Stress

2020 ◽  
Vol 8 (2) ◽  
pp. 92
Author(s):  
Yoyon Arif ◽  
Erna Sulistiowati
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Fluid Shear Stress ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Vascular Endothelial Cadherin

Sel endotel melapisi lumen pembuluh darah sehingga menyebabkan paparan langsung aliran darah dan timbul gaya hemodinamik shear stress. Vascular Endothelial (VE) Cadherin merupakan salah satu struktur penghubung antar sel yang berperan mencegah terlepasnya sel endotel dari membran dasar. Paparan glukosa tinggi menyebabkan stress oksidatif sehingga sel endotel mengalami apoptosis dan nekrosis dan terlepas. Penelitian ini bertujuan mempelajari efek paparan glukosa tinggi dan fluid shear stress terhadap morfologi, struktur VE-Cadherin dan densitas sel endotel pada kultur sel endotel HUVECs (Human Vein Endothelial Cells Culture).Metode Penelitian eksperimental laboratorium dengan  metode HUVECs yang dipapar d-glukosa 22 mM selama 7 hari. Shear stress dibangkitkan dengan alat cone and plate 10 dyne/cm2 selama 5, 8, 12 dan 15 menit. Pulasan VE-Cadherin dengan imunohistokimia. Data dianalisis dengan metode statistik. Signifikan pada p<0,05.Hasil Shear stress selama 15 menit menyebabkan perubahan bentuk sel endotel  menjadi lebih panjang dan inti sel lebih pipih. Paparan glukosa tinggi dan fluid shear stress menyebabkan penurunan skor VE-Cadherin dan densitas sel endotel secara signifikan Penurunan skor VE-Cadherin berpengaruh langsung terhadap penurunan densitas sel endotel.Kesimpulan. Paparan glukosa tinggi dan fluid shear stress menyebabkan kerusakan struktur VE-Cadherin sehingga terjadi peningkatan apoptosis dan nekrosis sel endotel.

Physiological fluid shear stress causes downregulation of endothelin-1 mRNA in bovine aortic endothelium

1992 ◽  
Vol 263 (2) ◽  
pp. C389-C396 ◽  
Author(s):  
A. Malek ◽  
S. Izumo
Keyword(s):  
Shear Stress ◽  
Fluid Shear Stress ◽  
Fluid Velocity ◽  
Low Frequency ◽  
Turbulent Shear ◽  
Specific Response ◽  
Dependent Manner ◽  
Fluid Shear ◽  
Endothelin 1

We report here that the level of endothelin-1 (ET-1) mRNA from bovine aortic endothelial cells grown in vitro is rapidly (within 1 h of exposure) and significantly (fivefold) decreased in response to fluid shear stress of physiological magnitude. The downregulation of ET-1 mRNA occurs in a dose-dependent manner that exhibits saturation above 15 dyn/cm2. The decrease is complete prior to detectable changes in endothelial cell shape and is maintained throughout and following alignment in the direction of blood flow. Peptide levels of ET-1 secreted into the media are also reduced in response to fluid shear stress. Cyclical stretch experiments demonstrated no changes in ET-1 mRNA, while increasing media viscosity with dextran showed that the downregulation is a specific response to shear stress and not to fluid velocity. Although both pulsatile and turbulent shear stress of equal time-average magnitude elicited the same decrease in ET-1 mRNA as steady laminar shear (15 dyn/cm2), low-frequency reversing shear stress did not result in any change. These results show that the magnitude as well as the dynamic character of fluid shear stress can modulate expression of ET-1 in vascular endothelium.

Role of cadherins and plakoglobin in interendothelial adhesion under resting conditions and shear stress

1997 ◽  
Vol 273 (5) ◽  
pp. H2396-H2405 ◽  
Author(s):  
Hans-Joachim Schnittler ◽  
Bernd Püschel ◽  
Detlev Drenckhahn
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Time Course ◽  
Fluid Shear Stress ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Arterial Endothelial Cells

The role of cadherins and the cadherin-binding cytosolic protein plakoglobin in intercellular adhesion was studied in cultured human umbilical venous endothelial cells exposed to fluid shear stress. Extracellular Ca2+depletion (<10−7 M) caused the disappearance of both cadherins and plakoglobin from junctions, whereas the distribution of platelet endothelial cell adhesion molecule 1 (PECAM-1) remained unchanged. Cells stayed fully attached to each other for several hours in low Ca2+ but began to dissociate under flow conditions. At the time of recalcification, vascular endothelial (VE) cadherin and β-catenin became first visible at junctions, followed by plakoglobin with a delay of ∼20 min. Full fluid shear stress stability of the junctions correlated with the time course of the reappearance of plakoglobin. Inhibition of plakoglobin expression by microinjection of antisense oligonucleotides did not interfere with the junctional association of VE-cadherin, PECAM-1, and β-catenin. The plakoglobin-deficient cells remained fully attached to each other under resting conditions but began to dissociate in response to flow. Shear stress-induced junctional dissociation was also observed in cultures of plakoglobin-depleted arterial endothelial cells of the porcine pulmonary trunk. These observations show that interendothelial adhesion under hydrodynamic but not resting conditions requires the junctional location of cadherins associated with plakoglobin. β-Catenin cannot functionally compensate for the junctional loss of plakoglobin, and PECAM-1-mediated adhesion is not sufficient for monolayer integrity under flow.

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