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Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo.
Schnoor, Michael Lai, Frank P L Zarbock, Alexander Kläver, Ruth Polaschegg, Christian Schulte, Dörte Weich, Herbert A Oelkers, J Margit Vestweber, Dietmar
Schnoor, Michael
Lai, Frank P L
Zarbock, Alexander
Kläver, Ruth
Polaschegg, Christian
Schulte, Dörte
Weich, Herbert A
Oelkers, J Margit
Vestweber, Dietmar
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2011-08-01
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Abstract
Neutrophil extravasation and the regulation of vascular permeability require dynamic actin rearrangements in the endothelium. In this study, we analyzed in vivo whether these processes require the function of the actin nucleation-promoting factor cortactin. Basal vascular permeability for high molecular weight substances was enhanced in cortactin-deficient mice. Despite this leakiness, neutrophil extravasation in the tumor necrosis factor-stimulated cremaster was inhibited by the loss of cortactin. The permeability defect was caused by reduced levels of activated Rap1 (Ras-related protein 1) in endothelial cells and could be rescued by activating Rap1 via the guanosine triphosphatase (GTPase) exchange factor EPAC (exchange protein directly activated by cAMP). The defect in neutrophil extravasation was caused by enhanced rolling velocity and reduced adhesion in postcapillary venules. Impaired rolling interactions were linked to contributions of β(2)-integrin ligands, and firm adhesion was compromised by reduced ICAM-1 (intercellular adhesion molecule 1) clustering around neutrophils. A signaling process known to be critical for the formation of ICAM-1-enriched contact areas and for transendothelial migration, the ICAM-1-mediated activation of the GTPase RhoG was blocked in cortactin-deficient endothelial cells. Our results represent the first physiological evidence that cortactin is crucial for orchestrating the molecular events leading to proper endothelial barrier function and leukocyte recruitment in vivo.
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Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. 2011, 208 (8):1721-35 J. Exp. Med.
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en
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1540-9538