A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Tzima, Ellie; Irani-Tehrani, Mohamed; Kiosses, William B.; Dejana, Elisabetta; Schultz, David; Engelhardt, Britta; Cao, Gaoyuan; DeLisser, Horace M.; Schwartz, Martin A.

doi:10.1038/nature03952

Cited by 1,490 publications

(1,492 citation statements)

References 29 publications

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“…As cortical actin dynamics and tension have been shown to control cadherin adhesion at adherens junctions (Engl et al , 2014) and VE‐cadherin is required for shear stress sensing and mechanotransduction (Tzima et al , 2005), we investigated whether arterial endothelial cell binding to laminin 511 or 411 affects adherens junction tension using a dual pipette‐pulling assay (Fig 5A). HUAECs were allowed to bind to laminin 411‐ or laminin 511‐coated beads.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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“…11 Interest in the precise mechanisms by which endothelial cells sense and respond to mechanical signals arises from a now well-established correlation between spatial and temporal variations in hemodynamic shear stress and the focal nature of atherosclerotic lesions. Candidate cellular structures responsible for mechanotransduction in ECs include FAs, plasma membrane subdomains, 4,43 cell-cell junctions, 52 and others. It has not yet been shown, however, that physiological shear stress results in sufficient stress in these regions to directly activate signaling.…”

Section: Relationship Between Stress and Endothelial Cell Mechanotranmentioning

confidence: 99%

“…A recent report by Tzima and colleagues suggests that PECAM-1, along with adapter molecules may constitute a force-sensitive system which indirectly activates integrin molecules. 52 In that study, both shear stress and bead pulling were used as forcing functions to activate integrins in endothelial cells. Since cell junctions were not explicitly included in the present model, it is not yet clear that bead pulling and shear stress elicit comparable stresses at cell junctions.…”

Section: Relationship Between Stress and Endothelial Cell Mechanotranmentioning

confidence: 99%

Finite-Element Stress Analysis of a Multicomponent Model of Sheared and Focally-Adhered Endothelial Cells

et al. 2007

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Hemodynamic forces applied at the apical surface of vascular endothelial cells may be redistributed to and amplified at remote intracellular organelles and protein complexes where they are transduced to biochemical signals. In this study we sought to quantify the effects of cellular material inhomogeneities and discrete attachment points on intracellular stresses resulting from physiological fluid flow. Steady-state shear-and magnetic bead-induced stress, strain, and displacement distributions were determined from finite-element stress analysis of a cell-specific, multicomponent elastic continuum model developed from multimodal fluorescence images of confluent endothelial cell (EC) monolayers and their nuclei. Focal adhesion locations and areas were determined from quantitative total internal reflection fluorescence microscopy and verified using green fluorescence protein-focal adhesion kinase (GFP-FAK). The model predicts that shear stress induces small heterogeneous deformations of the endothelial cell cytoplasm on the order of <100 nm. However, strain and stress were amplified 10-100-fold over apical values in and around the high-modulus nucleus and near focal adhesions (FAs) and stress distributions depended on flow direction. The presence of a 0.4 μm glycocalyx was predicted to increase intracellular stresses by ~2-fold. The model of magnetic bead twisting rheometry also predicted heterogeneous stress, strain, and displacement fields resulting from material heterogeneities and FAs. Thus, large differences in moduli between the nucleus and cytoplasm and the juxtaposition of constrained regions (e.g. FAs) and unattached regions provide two mechanisms of stress amplification in sheared endothelial cells. Such phenomena may play a role in subcellular localization of early mechanotransduction events.

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“…Cells have been reported to be stimulated through the activation of, e.g., integrins, G-protein receptors, tyrosine kinase receptors, or ion channels (reviewed in Lehoux and Tedgui, 2003). Especially the interaction complex involving CD31/PECAM1, VECadherin, and VEGFR2/KDR/FLK1 has been well documented (Tzima et al, 2005). Besides a molecular sensor complex, an ultrastructural adaptation for mechanosensing, called a primary cilium, has been described (Singla and Reiter, 2006).…”

Section: Introductionmentioning

confidence: 99%

Primary cilia sensitize endothelial cells for fluid shear stress

Hierck

Heiden

Alkemade

et al. 2008

Developmental Dynamics

155

106

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Primary cilia are mechanosensors for fluid shear stress, and are involved in a number of syndromes and congenital anomalies. We identified endothelial cilia in areas of low shear stress in the embryonic heart. The objective of the present study was to demonstrate the role of primary cilia in mechanosensing. Ciliated embryonic endothelial cells were cultured from the heart, and non-ciliated cells from the arteries. Nonciliated cells that were subjected to fluid shear stress showed significantly less induction of the shear marker Krü ppel-Like Factor-2, as compared to ciliated cells. In addition, ciliated cells from which the cilia were chemically removed show a similar decrease in flow response. This shows that primary cilia sensitize endothelial cells for fluid shear stress. In addition, we targeted and stabilized the connection of the cilium to the cytoplasm by treatment with Colchicine and Taxol/Paclitaxel, respectively, and show that microtubular integrity is essential to sense shear stress. Developmental Dynamics 237:725-735, 2008.

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A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Cited by 1,490 publications

References 29 publications

Endothelial basement membrane laminin 511 is essential for shear stress response

Endothelial basement membrane laminin 511 is essential for shear stress response

Finite-Element Stress Analysis of a Multicomponent Model of Sheared and Focally-Adhered Endothelial Cells

Primary cilia sensitize endothelial cells for fluid shear stress

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