A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress

Liu, Yunhao; Collins, Caitlin; Kiosses, William B.; Murray, Ann; Joshi, Monika; Shepherd, Tyson R.; Fuentes, Ernesto J.; Tzima, Ellie

doi:10.1083/jcb.201207115

Cited by 61 publications

(78 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This idea also fits well with the observation that onset of unidirectional laminar shear initially activates the inflammatory pathways, but these pathways are downregulated at later times as cells align and the antiinflammatory pathways become dominant (55). The mechanistic basis for these effects is unknown, but a tantalizing clue comes from the finding that production of ROS by the NADPH oxidase complex in response to flow requires association of VE-cadherin with the oxidase complex through the polarity protein PAR3 (56). A link between alignment and atherosclerosis in vivo is supported by studies on syndecan4 -/-mice, in which ECs fail to align in flow; on a hypercholesterolemic background, these mice show increased atherosclerosis, including lesions in regions of laminar flow that are normally protected (57).…”

Section: Plaque Progression and Remodelingsupporting

confidence: 69%

Endothelial fluid shear stress sensing in vascular health and disease

Baeyens

Bandyopadhyay

Coon

et al. 2016

Journal of Clinical Investigation

467

407

View full text Add to dashboard Cite

Section: Plaque Progression and Remodelingsupporting

confidence: 69%

Endothelial fluid shear stress sensing in vascular health and disease

Baeyens

Bandyopadhyay

Coon

et al. 2016

Journal of Clinical Investigation

467

407

View full text Add to dashboard Cite

“…Flow induces TIAM1 association with VE-cadherin and the Par3-Par6-aPKC polarity complex at the downstream edge of the cell. Surprisingly, this role for TIAM1 does not require GEF activity but is required for coupling of Rac1 with its effector, the NADPH oxidase complex and production of reactive oxygen (Liu et al, 2013). These data point toward a highly intricate polarization mechanism involving a non-canonical function for TIAM1 in conjunction with membrane receptors and polarity proteins.…”

Section: Mechanosensors Of Endothelial Shear Stressmentioning

confidence: 94%

“…Interestingly, Rac1 activation is polarized toward the downstream edge of the cell relative to the flow direction, which mediates endothelial cell alignment. Recent work, however, showed that Rac1 activation by flow requires PECAM-1, acting through the Rac GEF VAV2; however, its spatial polarization requires a distinct GEF, TIAM1 (Liu et al, 2013). Flow induces TIAM1 association with VE-cadherin and the Par3-Par6-aPKC polarity complex at the downstream edge of the cell.…”

Section: Mechanosensors Of Endothelial Shear Stressmentioning

confidence: 99%

Flow-dependent cellular mechanotransduction in atherosclerosis

Conway

Schwartz

2013

Journal of Cell Science

View full text Add to dashboard Cite

SummaryAtherosclerosis depends on risk factors such as hyperlipidemia, smoking, hypertension and diabetes. Although these risk factors are relatively constant throughout the arterial circulation, atherosclerotic plaques occur at specific sites where flow patterns are disturbed, with lower overall magnitude and complex changes in speed and direction. Research over the past few decades has provided new insights into the cellular mechanisms of force transduction and how mechanical effects act in concert with conventional risk factors to mediate plaque formation and progression. This Commentary summarizes our current understanding of how mechanotransduction pathways synergize with conventional risk factors in atherosclerosis. We attempt to integrate cellular studies with animal and clinical data, and highlight major questions that need to be answered to develop more effective therapies.

show abstract

“…25 NF-κB activation in response to acute flow is also dependent on degradation of IκB by Rac GTPase-induced reactive oxygen species (ROS). 26 Therefore, both ROS and focal adhesion kinase signaling events are essential for nuclear translocation and transcriptional activity of NF-κB in response to acute flow. Although it has been shown that the content of extracellular matrix differs between atheroprone (fibronectin-rich) 27 and atheroprotected (collagen-rich) regions, 28 disturbed flow in combination with intergrin-fibronectin interaction is required for sustained NF-κB and JNK activation.. 29,30 Furthermore, a signaling pathway involving the adaptor protein Shc has been suggested as the molecular switch that coordinates interaction between cell-cell and cell-extracellular matrix, resulting in the initial extracellular matrix-independent activation of extracellular-signal-regulated kinase (ERK) on acute onset of flow to follow by extracellular matrix-dependent NF-κB activation.…”

Section: Signaling To Nf-κbmentioning

confidence: 99%

Mechanoresponsive Networks Controlling Vascular Inflammation

Bryan

Duckles

Feng

et al. 2014

ATVB

101

View full text Add to dashboard Cite

Atherosclerosis is characterized by an accumulation of smooth muscle cells and a buildup of lipid-rich foamy macrophages within the arterial wall, which can lead to lumen narrowing and reduced blood flow or to a complete arterial blockage after plaque rupture.1 Atherosclerosis development is influenced by several factors, including age, sex, cholesterol level, and obesity.2 Despite the systemic nature of these risk factors, atherosclerotic plaque formation is remarkably localized, forming predominantly around arterial branches and the inner curvature of bends. Blood flow is a major influence on localized atherosclerosis development, because the location of plaques correlates with specific flow patterns.3 Regions of the artery wall where blood flow is low or disturbed are prone to atherosclerosis, whereas arterial regions exposed to high flow are protected. 4 Flow affects molecular transport from the bloodstream to the endothelium, because different flow conditions directly influence the local concentration of molecules and their interaction time with the artery wall. In addition to modifying mass transport, blood flow exposes the endothelial layer to wall shear stress (WSS; the friction-like drag between the fluid and the arterial wall surface) and other mechanical actions.5 Flowinduced WSS varies over time in both magnitude and direction in a characteristic pattern that is dependent on the location within the arterial system (Figure 1). 6,7 There are several metrics that can be used to characterize a stress pattern (Figure 1), including time-averaged WSS magnitude, oscillatory shear index (a figure of merit describing the fraction of the profile that the instantaneous WSS opposes the mean WSS direction during one oscillation), angular direction of shear stress, and harmonic frequency components. There is ongoing debate on the relative importance of these parameters in endothelial responses to WSS; however, it is plausible that mechanoreceptors integrate multiple mechanical parameters to convert information on WSS magnitude, frequency, and direction into biochemical signals. 8 Although many interrelated signaling networks have been identified, understanding of mechanically triggered signaling is still developing. Here, we review established, biochemically triggered, inflammatory mechanisms before discussing recent progress in uncovering the role of mechanical cues in inflammatory pathways and possible future directions of research. Please see http://atvb.ahajournals.org/site/misc/ ATVB_in_Focus.xhtml for all articles published in this series. Blood Flow and Vascular InflammationAtherosclerosis is promoted by the recruitment of monocytes from the blood to the vessel wall via interactions with © 2014 American Heart Association, Inc. Abstract-Atherosclerosis is a chronic inflammatory disease of arteries that develops preferentially at branches and bends that are exposed to disturbed blood flow. Vascular function is modified by flow, in part, via the generation of mechanical forces that alter multiple physiological ...

show abstract

A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress

Abstract: The GEF Tiam1 acts as a novel molecular link to the VE-cadherin–p67phox–Par3 polarity complex, leading to localized activation of Rac1 and NADPH oxidase in response to fluid flow.

Cited by 61 publications

References 45 publications

Endothelial fluid shear stress sensing in vascular health and disease

Endothelial fluid shear stress sensing in vascular health and disease

Flow-dependent cellular mechanotransduction in atherosclerosis

Mechanoresponsive Networks Controlling Vascular Inflammation

Contact Info

Product

Resources

About