Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment

Tzima, Ellie; Pozo, Miguel Á. del; Shattil, Sanford J.; Chien, Shu; Schwartz, Martin A.

doi:10.1093/emboj/20.17.4639

Cited by 512 publications

(556 citation statements)

References 52 publications

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“…We verified that exposure of EC to 48 h of 8-10 dyn/cm 2 sinusoidal WSS stimuli induced cell elongation and alignment and reorganization of cell monolayer. The EC elongation, previously reported by other groups (Remuzzi et al 1984;Tzima et al 2001), demonstrates the capability of the CPD to induce flow-dependent cell morphological adaptations. In addition, the capability of the system to induce flow-dependent morphological adaptations has been further verified by exposing HUVECs to the atheroprotective and atheroprone WSS waveforms, as calculated in a model of the carotid bifurcation (Dai et al 2004).…”

Section: Discussionsupporting

confidence: 71%

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers

et al. 2016

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Endothelial cells are constantly exposed to blood flow and the resulting frictional force, the wall shear stress, varies in magnitude and direction with time, depending on vasculature geometry. Previous studies have shown that the structure and function of endothelial cells, and ultimately of the vessel wall, are deeply affected by the nature of wall shear stress waveforms. To investigate the in vitro effects of these stimuli, we developed a compact, programmable, realtime operated system based on cone-and-plate geometry, that can be used within a standard cell incubator. To verify the capability to replicate realistic shear stress waveforms, we calculated both analytically and numerically to what extent the system is able to correctly deliver the stimuli defined by the user at plate level. Our results indicate that for radii greater than 25 mm, the shear stress is almost uniform and directly proportional to cone rotation velocity. We further established that using a threshold of 10 Hz of wall shear stress waveform frequency components, oscillating flow conditions can be reproduced on cell monolayer surface. Finally, we verified the capability of the system to perform long-term flow exposure experiments ensuring sterility and cell culture viability on human umbilical vein endothelial cells exposed to unidirectional and oscillating shear stress. In conclusion, the system we developed is a highly dynamic, easy to handle, and able to generate pulsatile and unsteady oscillating wall shear stress waveforms. This system can be used to investigate the effects of realistic stimulations on endothelial cells, similar to those exerted in vivo by blood flow.

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Section: Discussionsupporting

confidence: 71%

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers

et al. 2016

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“…β1‐Integrin‐containing focal adhesions (FAs) have been shown to be important for shear stress mechanotransduction (Davies et al , 1994; Tzima et al , 2001), and changes in their size and number are regulated in response to the intensity of the mechanical load, thereby controlling the strength of adhesion (Jalali et al , 2001). However, few studies have examined FA in vivo (van Geemen et al , 2014).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro studies using HUVECs or BAEC plated onto fibronectin have shown that endothelial cells modulate the avidity and affinity of adhesion complexes upon increased shear stress, which results in increased adhesion strength and intracellular signalling (Urbich et al , 2000; Jalali et al , 2001; Tzima et al , 2001). This is consistent with the small adhesion complexes observed in the endothelium of Tek‐Cre::Lama5 −/− arteries, which lack laminin 511 and have a reduced shear stress response, and the larger adhesion complexes in Lama4 −/− vessels, which express laminin 511 and have an enhanced response to shear stress.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is very difficult to prove, the absence of a single molecule such as laminin 511 from the basement membrane is unlikely to affect the overall stiffness of the matrix, plus the stiffness of the glass on which isolated laminins were plated in the AFM experiments is likely to override any laminin‐specific effects. It is therefore likely that biochemical signals derived from endothelial adhesion to laminin 511 act downstream to regulate actin arrangements and thereby cortical stiffness and mechanotransduction processes (Hutcheson & Griffith, 1996; Tzima et al , 2001). Candidate downstream signalling molecules include RhoA, which has been implicated in force generation via β1‐integrins (Schiller et al , 2013) and shear responses (Jalali et al , 1998; Tzima et al , 2001), and Src kinase (Huveneers & Danen, 2009; Martinez‐Rico et al , 2010).…”

Section: Discussionmentioning

confidence: 99%

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Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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“…This force is transmitted through the cytoskeleton to FAs. Integrins have been shown to respond to fluid flow (Tzima et al, 2001) and to be locally activated at the downstream edge (Goldfinger et al, 2008). However, this may be due to increased integrin-ECM ligation.…”

Section: Introductionmentioning

confidence: 99%

A model of localised Rac1 activation in endothelial cells due to fluid flow

Bogle¹,

Ridley²

2011

Journal of Theoretical Biology

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Endothelial cells respond to fluid flow by elongating in the direction of flow. Cytoskeletal changes and activation of signalling molecules have been extensively studied in this response, including: activation of receptors by mechano-transduction, actin filament alignment in the direction of flow, changes to cell-substratum adhesions, actin-driven lamellipodium extension, and localised activation of Rho GTPases. To study this process we model the force over a single cell and couple this to a model of the Rho GTPases, Rac and Rho, via a Kelvin-body model of mechanotransduction. It is demonstrated that a mechano-transducer that can respond to the normal component of the force is likely to be a necessary component of the signalling network in order to establish polarity. Furthermore, the rate-limiting step of Rac1 activation is predicted to be conversion of Rac-GDP to Rac-GTP, rather than activation of upstream components. Modelling illustrates that the aligned endothelial cell morphology could attenuate the signalling network.

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Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment

Cited by 512 publications

References 52 publications

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers

Endothelial basement membrane laminin 511 is essential for shear stress response

A model of localised Rac1 activation in endothelial cells due to fluid flow

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