The RhoA Guanine Nucleotide Exchange Factor, LARG, Mediates ICAM-1–Dependent Mechanotransduction in Endothelial Cells To Stimulate Transendothelial Migration

Lessey-Morillon, Elizabeth C.; Osborne, Lukas D.; Monaghan-Benson, Elizabeth; Guilluy, Christophe; O’Brien, E. Timothy; Superfine, R.; Burridge, Keith

doi:10.4049/jimmunol.1302525

Cited by 53 publications

(65 citation statements)

References 60 publications

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“…Interestingly, upon mechanical tension both proteins have been reported to induce RhoA activity. 96,97 In support of a prominent role for ICAM-1, our data show that depletion of ICAM-1 in TNF-a-stimulated endothelial cells resulted in an increase of neutrophil-induced dextran leakage compared to control endothelial cells, although the levels did not reach the levels when RhoA was silenced. 93 PECAM-1 however appeared not to be involved in maintenance of barrier function, as depletion in ECs had no effect on neutrophilinduced dextran leakage and neutrophil transmigration numbers.…”

Section: Actin Regulation During Leukocyte Temsupporting

confidence: 61%

Leukocyte transendothelial migration: A local affair

2016

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Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves leukocytes, blood vessels and molecular mediators with the purpose to eliminate the initial cause of cell injury and to initiate tissue repair. Inflammation is tightly regulated by the body and is associated with transient crossing of leukocytes through the blood vessel wall, a process called transendothelial migration (TEM) or diapedesis. TEM is a close collaboration between leukocytes on one hand and the endothelium on the other. Limiting vascular leakage during TEM but also when the leukocyte has crossed the endothelium is essential for maintaining vascular homeostasis. Although many details have been uncovered during the recent years, the molecular mechanisms from the vascular part that drive TEM still shows significant gaps in our understanding. This review will focus on the local signals that are induced in the endothelium that regulate leukocyte TEM and simultaneous preservation of endothelial barrier function.

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Section: Actin Regulation During Leukocyte Temsupporting

confidence: 61%

Leukocyte transendothelial migration: A local affair

2016

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“…Durotaxis requires the sensing of substrate stiffness by adhesion molecule tugging. 74 The identification of podoprints or adhesive filopodia to probe the EC surface, [75][76][77] together with the recent results obtained by pulling on intercellular adhesion molecule-1 (ICAM-1) using magnetic tweezers 78 certainly support a model of leukocyte-mediated tugging to sense and regulate local EC stiffness.…”

Section: Cross Talk Between Ec Stiffness and Leukocyte Behaviormentioning

confidence: 99%

“…59 In agreement with this, repetitive pulling on adherent anti-ICAM-1-coated magnetic beads using magnetic tweezers increased local EC stiffness. 78 This stiffening response was accompanied by Rho activation and sensitive to inhibitors of actomyosin-based contractility and Rho kinase. The authors identified the RhoGEF LARG (RhoGEF12) as a key upstream activator of Rho.…”

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confidence: 99%

Between Rho(k) and a Hard Place

Huveneers

Daemen

Hordijk

2015

Circulation Research

154

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Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. vascular stiffening) and the various external cues that regulate this. In addition, we will discuss the relationship between endothelial contractility and leukocyte extravasation and finally address (future) possibilities to therapeutically target ECs to reduce chronic, stiffness-related, vascular inflammation. Systemic Regulation of Vascular StiffnessArterial stiffness is strongly associated with high blood pressure, as well as with aging, and serves as an independent predictor of human cardiovascular disease. An elevation in arterial stiffness increases systolic blood pressure, thereby promoting cardiac hypertrophy, and decreases the diastolic blood pressure which is a trigger for developing myocardial ischemia. 7 Aortic stiffness also affects the microcirculation and vice versa, microcirculatory changes affect aortic stiffness. Stiffening of the aortic wall leads to increased pulse wave velocity (PWV) and premature reflected waves with elevated systolic and pulsatile central hemodynamic load resulting in microcirculatory damages in peripheral tissues. Conversely, microvasculature remodeling elevates systemic vascular resistance and pulse wave reflection, which stiffens the aortic wall, indicating that the endothelium has both a responsive and a causal role in vascular stiffening. 7 Increased PWV accurately estimates arterial wall stiffness and has recently been included in official hypertension guidelines. PWV values increase with age, and increases in aortic PWV is a g...

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“…α-actinin-4), increased formation of F-actin stress fibers, RhoA activity and ROCK-myosin-based contraction forces (Heemskerk et al, 2014). ICAM1 clustering induces force-dependent positive feedback-signaling in inflamed ECs, resulting in the amplification of ICAM1 signaling towards the F-actin cytoskeleton and improved leukocyte adhesion (Lessey-Morillon et al, 2014;Schaefer et al, 2014). Accordingly, the application of tension on ICAM1 in order to mimic leukocyte pulling forces further promotes RhoA activity, myosin-based contractile forces and EC stiffening (Fig.…”

Section: Box 1 Mechanotransduction In Inflammatory Diseasementioning

confidence: 99%

Cell-stiffness-induced mechanosignaling – a key driver of leukocyte transendothelial migration

Schaefer

Hordijk

2015

Journal of Cell Science

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The breaching of cellular and structural barriers by migrating cells is a driving factor in development, inflammation and tumor cell metastasis. One of the most extensively studied examples is the extravasation of activated leukocytes across the vascular endothelium, the inner lining of blood vessels. Each step of this leukocyte transendothelial migration (TEM) process is regulated by distinct endothelial adhesion receptors such as the intercellular adhesion molecule 1 (ICAM1). Adherent leukocytes exert force on these receptors, which sense mechanical cues and transform them into localized mechanosignaling in endothelial cells. In turn, the function of the mechanoreceptors is controlled by the stiffness of the endothelial cells and of the underlying substrate representing a positive-feedback loop. In this Commentary, we focus on the mechanotransduction in leukocytes and endothelial cells, which is induced in response to variations in substrate stiffness. Recent studies have described the first key proteins involved in these mechanosensitive events, allowing us to identify common regulatory mechanisms in both cell types. Finally, we discuss how endothelial cell stiffness controls the individual steps in the leukocyte TEM process. We identify endothelial cell stiffness as an important component, in addition to locally presented chemokines and adhesion receptors, which guides leukocytes to sites that permit TEM.

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The RhoA Guanine Nucleotide Exchange Factor, LARG, Mediates ICAM-1–Dependent Mechanotransduction in Endothelial Cells To Stimulate Transendothelial Migration

Cited by 53 publications

References 60 publications

Leukocyte transendothelial migration: A local affair

Leukocyte transendothelial migration: A local affair

Between Rho(k) and a Hard Place

Cell-stiffness-induced mechanosignaling – a key driver of leukocyte transendothelial migration

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