Role of TRPV4 in the Mechanotransduction of Shear Stress in Endothelial Cells

2006 ◽  
pp. 399-410
Keyword(s):  
Endothelial Cells ◽  
Shear Stress

scholarly journals Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+ signaling in vascular endothelial cells

2018 ◽  
Vol 315 (5) ◽  
pp. H1477-H1485 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Hiromi Imamura ◽  
Joji Ando
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Atp Release ◽  
Vascular Endothelial ◽  
The Novel ◽  
Caveolin 1 ◽  
Atp Generation

Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.

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.

scholarly journals Revealing the Role of Phosphatidylserine in Shear Stress–Mediated Protection in Endothelial Cells

Endothelium ◽  
2008 ◽  
Vol 15 (4) ◽  
pp. 225-230 ◽  
Author(s):  
Julie K. Freed ◽  
Michael R. Shortreed ◽  
Christopher J. Kleefisch ◽  
Lloyd M. Smith ◽  
Andrew S. Greene
Keyword(s):  
Endothelial Cells ◽  
Shear Stress

Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells

1994 ◽  
Vol 267 (3) ◽  
pp. C753-C758 ◽  
Author(s):  
M. J. Kuchan ◽  
H. Jo ◽  
J. A. Frangos
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
G Protein ◽  
G Proteins ◽  
No Production ◽  
Dependent Manner ◽  
Protein Activation ◽  
Synthase Inhibitor

Exposure of cultured endothelial cells to shear stress resulting from well-defined fluid flow stimulates the production of nitric oxide (NO). We have established that an initial burst in production is followed by sustained steady-state NO production. The signal transduction events leading to this stimulation are not well understood. In the present study, we examined the role of regulatory guanine nucleotide binding proteins (G proteins) in shear stress-mediated NO production. In endothelial cells not exposed to shear stress, AIF4-, a general activator of G proteins, markedly elevated the production of guanosine 3',5'-cyclic monophosphate (cGMP). Pretreatment with NO synthase inhibitor N omega-nitro-L-arginine completely blocked this stimulation. Incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a general G protein inhibitor, blocked the flow-mediated burst in cGMP production in a dose-dependent manner. Likewise, GDP beta S inhibited NOx (NO2 + NO3) production for the 1st h. However, inhibition was not detectable between 1 and 3 h. Pertussis toxin (PTx) had no effect on the shear response at any time point. The burst in NO production caused by a change in shear stress appears to be dependent on a PTx-refractory G protein. Sustained shear-mediated production is independent of G protein activation.

scholarly journals Role of cFOS in mechanosensitive transcriptional regulation in diabetes associated atherosclerosis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A Khan ◽  
M Lee ◽  
A Watson ◽  
S Maxwell ◽  
M Cooper ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Myocardial Dysfunction ◽  
Transcriptional Profile ◽  
Gene Set Enrichment Analysis ◽  
Regulation Of Transcription ◽  
Gene Markers ◽  
Low Shear Stress ◽  
Low Shear

Abstract   Atherosclerosis, as manifested clinically by myocardial infarction, stroke and peripheral vascular disease, is a major contributor to cardiovascular disease, the leading cause of death in patients with diabetes. The lipid-laden plaque development within the arterial vessel wall is a progressive process initiated with endothelial cell activation and monocyte adhesion. These cellular events occur primarily at the regions of blood vessels exposed to turbulent blood flow (TBF) and low shear stress such as vascular bends and bifurcations. Exposure of the vascular cells to chronic hyperglycaemia and TBF induces a proatherogenic transcriptional profile. Studies have shown that shear stress regulates vascular pathophysiology via differential regulation of transcription factors (TFs) such as KLF4, EGR1 and AP-1, hence named as mechanosensitive TFs. AP-1 is a heterodimer composed of FOS, Jun and ATF family of TFs. Studies have shown that it is activated by low shear stress in cultured endothelial cells. Increasing evidence supports the vital role of AP-1 family members in inflammation and diabetes-induced myocardial dysfunction. However, gene targets and the mechanisms underlying hyperglycemia-induced activation of AP-1 transcription factor cFOS in vascular regions exposed to TBF are not known.Although a novel approach not previously studied in diabetes associated atherosclerosis, we used a single cell RNA sequencing (scRNA-seq) approach to identify endothelial cells from TBF regions of aorta. Diabetes was induced with streptozotocin (STZ) in Apoe−/− mice and followed for 10 weeks. Cells from digested aortae of control and diabetic mice were subjected to scRNA-seq using 10X Genomics system and Illumina Nova-seq 6000. Unsupervised graph based clustering grouped cells into fourteen cell clusters with similar gene expression profile. We applied a list of mechanosensitive gene markers including EGR1, cFOS, Junb and ICAM1 in scRNA-seq analysis to identify endothelial cells from TBF regions of aorta. This approach identified atheroprone endothelial cells exposed to persistent TBF that showed a distinct transcriptional profile with more than six hundred genes differentially expressed. Importantly, cFOS was the most significantly upregulated gene in endothelial cells exposed to TBF. We next generated adiabetes associated transcriptional signature unique to endothelial cells exposed to TBF as compared to all other cell types in the aorta. We identified several genes in endothelial cells exposed to TBF and hyperglycaemia uniquely dysregulated in diabetic Apoe−/− mice as compared to control mice (cut off = FDR&lt;0.05, fold change at least 2-fold). Gene set enrichment analysis identified “fluid shear stress and atherosclerosis” as most significantly dysregulated pathway in endothelial cells. These novel findings indicate that AP-1 TF subunit cFOS is a potential therapeutic target in diabetes associated atherosclerosis that warrant further experimental exploration. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of Australia

A Novel Role of Id1 in Regulating Oscillatory Shear Stress-Mediated Lipid Uptake in Endothelial Cells

2018 ◽  
Vol 46 (6) ◽  
pp. 849-863 ◽  
Author(s):  
Kang Zhang ◽  
Yidan Chen ◽  
Tian Zhang ◽  
Lu Huang ◽  
Yi Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Oscillatory Shear ◽  
Lipid Uptake ◽  
Oscillatory Shear Stress

scholarly journals Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

2010 ◽  
Vol 298 (1) ◽  
pp. L105-L116 ◽  
Author(s):  
Sanjiv Kumar ◽  
Neetu Sud ◽  
Fabio V. Fonseca ◽  
Yali Hou ◽  
Stephen M. Black
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Catalase Activity ◽  
Serine Phosphorylation ◽  
Nitric Oxide Signaling ◽  
Enos Uncoupling ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Previous studies have indicated that acute increases in shear stress can stimulate endothelial nitric oxide synthase (eNOS) activity through increased PI3 kinase/Akt signaling and phosphorylation of Ser1177. However, the mechanism by which shear stress activates this pathway has not been adequately resolved nor has the potential role of reactive oxygen species (ROS) been evaluated. Thus, the purpose of this study was to determine if shear-mediated increases in ROS play a role in stimulating Ser1177 phosphorylation and NO signaling in pulmonary arterial endothelial cells (PAEC) exposed to acute increases in shear stress. Our initial studies demonstrated that although shear stress did not increase superoxide levels in PAEC, there was an increase in H2O2 levels. The increases in H2O2 were associated with a decrease in catalase activity but not protein levels. In addition, we found that acute shear stress caused an increase in eNOS phosphorylation at Ser1177 phosphorylation and a decrease in phosphorylation at Thr495. We also found that the overexpression of catalase significantly attenuated the shear-mediated increases in H2O2, phospho-Ser1177 eNOS, and NO generation. Further investigation identified a decrease in PKCδ activity in response to shear stress, and the overexpression of PKCδ attenuated the shear-mediated decrease in Thr495 phosphorylation and the increase in NO generation, and this led to increased eNOS uncoupling. PKCδ overexpression also attenuated Ser1177 phosphorylation through a posttranslational increase in catalase activity, mediated via a serine phosphorylation event, reducing shear-mediated increases in H2O2. Together, our data indicate that shear stress decreases PKCδ activity, altering the phosphorylation pattern catalase, leading to decreased catalase activity and increased H2O2 signaling, and this in turn leads to increases in phosphorylation of eNOS at Ser1177 and NO generation.

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