A Flow-Activated Chloride-Selective Membrane Current in Vascular Endothelial Cells

Barakat, Abdul I.; Leaver, Eric V.; Pappone, Pamela A.; Davies, Peter F.

doi:10.1161/01.res.85.9.820

Cited by 137 publications

(113 citation statements)

References 51 publications

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“…Mechanotransduction studies with fluid shear stress typically apply stresses on the order of 1-10 dynes/cm 2 (0.1-1.0 Pa) and observe changes in intracellular calcium and nitric oxide levels (22,27,29,38), ion channel activity (2,33), G protein activation (20), gene expression (15), and focal adhesion translocation (30). This level of stress, applied over a typical endothelial cell area on the order of 1,000 m 2 , results in nN-level shear forces.…”

Section: Discussionmentioning

confidence: 99%

Force-induced focal adhesion translocation: effects of force amplitude and frequency

Mack

Kaazempur-Mofrad²,

Karcher³

et al. 2004

American Journal of Physiology-Cell Physiology

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. Force-induced focal adhesion translocation: effects of force amplitude and frequency. Am J Physiol Cell Physiol 287: C954 -C962, 2004. First published June 9, 2004 10.1152/ajpcell. 00567.2003.-Vascular endothelial cells rapidly transduce local mechanical forces into biological signals through numerous processes including the activation of focal adhesion sites. To examine the mechanosensing capabilities of these adhesion sites, focal adhesion translocation was monitored over the course of 5 min with GFPpaxillin while applying nN-level magnetic trap shear forces to the cell apex via integrin-linked magnetic beads. A nongraded steady-load threshold for mechanotransduction was established between 0.90 and 1.45 nN. Activation was greatest near the point of forcing (Ͻ7.5 m), indicating that shear forces imposed on the apical cell membrane transmit nonuniformly to the basal cell surface and that focal adhesion sites may function as individual mechanosensors responding to local levels of force. Results from a continuum, viscoelastic finite element model of magnetocytometry that represented experimental focal adhesion attachments provided support for a nonuniform force transmission to basal surface focal adhesion sites. To further understand the role of force transmission on focal adhesion activation and dynamics, sinusoidally varying forces were applied at 0.1, 1.0, 10, and 50 Hz with a 1.45 nN offset and a 2.25 nN maximum. At 10 and 50 Hz, focal adhesion activation did not vary with spatial location, as observed for steady loading, whereas the response was minimized at 1.0 Hz. Furthermore, applying the tyrosine kinase inhibitors genistein and PP2, a specific Src family kinase inhibitor, showed tyrosine kinase signaling has a role in force-induced translocation. These results highlight the mutual importance of force transmission and biochemical signaling in focal adhesion mechanotransduction. mechanotransduction; endothelial cell; paxillin; viscoelastic model MECHANOTRANSDUCTION IS AN essential function of the cell, controlling its growth, proliferation, protein synthesis, and gene expression (8,18). Extensive data exist documenting the cellular responses to external force (15, 41, 44), but less is known about how force affects rapid biological signaling. Although integrins/focal adhesion sites (42), cytoskeleton constituents, G proteins (6), ion channels, intercellular junction proteins, and membrane biomolecules have all been identified as potential mechanosensors (6,16,42,43), we know little about the force level and frequency-dependent thresholds required to initiate mechanotransduction or the role of intracellular force transmission on mechanosensor activation. Biological readouts used to study mechanotransduction range from long-term gene expression and cell morphology changes (8, 26) to rapid variations in intracellular ion concentration and protein activity (8,26,42). Morphological and gene expression comparisons provide a robust marker of mechanotransduction, but the response is slow on the scale of hours, a...

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Section: Discussionmentioning

confidence: 99%

Force-induced focal adhesion translocation: effects of force amplitude and frequency

Mack

Kaazempur-Mofrad²,

Karcher³

et al. 2004

American Journal of Physiology-Cell Physiology

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“…This shearing stress therefore acts at a tangent to the wall to create a frictional force at the surface of the endothelium. Although shear stress has a very small magnitude in comparison to circumferential stress, the endothelial cells are equipped with numerous mechanosensors to detect this stress [20][21][22][23][24][25] . To maintain physiological levels of vessel wall shear stress, vascular tissues respond to changes in shear stress with acute adjustments in vascular tone (through vasodilation) 26) .…”

Section: Stimuli Regulating Endothelial Functionmentioning

confidence: 99%

Use of Ultrasound for Non-Invasive Assessment of Flow-Mediated Dilation

Stoner

Sabatier

2012

JAT

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The pathological complications of atherosclerosis, namely heart attacks and strokes, remain the leading cause of mortality in the Western world. Preceding atherosclerosis is endothelial dysfunction. There is therefore interest in the application of non-invasive clinical tools to assess endothelial function. The flow-mediated dilation (FMD) test is the standard tool used to assess endothelial function. Reduced FMD is an early marker of atherosclerosis and has been noted for its capacity to predict future cardiovascular disease events. This review discusses the measurement of endothelial function using ultrasound, with a focus on the FMD technique.

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“…Shear stress therefore acts at a tangent to the wall to create a frictional force at the surface of the endothelium. As endothelial cells are equipped with mechanosensors to detect this stress [62][63][64][65][66][67][68][69][70][71] , the vascular tissues respond accordingly with acute adjustments in vascular tone 72) . This vasodilatory response reflects alterations in the rate of production of endothelial-derived mediators, including NO, PGI2 and EHRF, which act locally to modulate vascular smooth muscle tone.…”

Section: Flow-mediated Dilationmentioning

confidence: 99%

There^|^rsquo;s More to Flow-Mediated Dilation Than Nitric Oxide

Stoner

Erickson

Young³

et al. 2012

JAT

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Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary.

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A Flow-Activated Chloride-Selective Membrane Current in Vascular Endothelial Cells

Cited by 137 publications

References 51 publications

Force-induced focal adhesion translocation: effects of force amplitude and frequency

Force-induced focal adhesion translocation: effects of force amplitude and frequency

Use of Ultrasound for Non-Invasive Assessment of Flow-Mediated Dilation

There^|^rsquo;s More to Flow-Mediated Dilation Than Nitric Oxide

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