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dc.contributor.authorSchnoor, Michael
dc.contributor.authorLai, Frank P L
dc.contributor.authorZarbock, Alexander
dc.contributor.authorKläver, Ruth
dc.contributor.authorPolaschegg, Christian
dc.contributor.authorSchulte, Dörte
dc.contributor.authorWeich, Herbert A
dc.contributor.authorOelkers, J Margit
dc.contributor.authorRottner, Klemens
dc.contributor.authorVestweber, Dietmar
dc.date.accessioned2012-02-06T14:40:51Z
dc.date.available2012-02-06T14:40:51Z
dc.date.issued2011-08-01
dc.identifier.citationCortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. 2011, 208 (8):1721-35 J. Exp. Med.en
dc.identifier.issn1540-9538
dc.identifier.pmid21788407
dc.identifier.doi10.1084/jem.20101920
dc.identifier.urihttp://hdl.handle.net/10033/209453
dc.description.abstractNeutrophil 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.
dc.language.isoenen
dc.subject.meshActinsen
dc.subject.meshAnimalsen
dc.subject.meshBlotting, Westernen
dc.subject.meshCapillary Permeabilityen
dc.subject.meshCell Adhesionen
dc.subject.meshCortactinen
dc.subject.meshEndothelial Cellsen
dc.subject.meshGTP Phosphohydrolasesen
dc.subject.meshGenotypeen
dc.subject.meshGuanine Nucleotide Exchange Factorsen
dc.subject.meshHumansen
dc.subject.meshIntercellular Adhesion Molecule-1en
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Mutant Strainsen
dc.subject.meshMicroscopy, Fluorescenceen
dc.subject.meshNeutrophilsen
dc.subject.meshOligonucleotidesen
dc.subject.meshRNA, Small Interferingen
dc.subject.meshSignal Transductionen
dc.subject.meshUmbilical Veinsen
dc.subject.meshrap1 GTP-Binding Proteinsen
dc.titleCortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo.en
dc.typeArticleen
dc.contributor.departmentMax Planck Institute for Molecular Biomedicine, D 48149 Münster, Germany.en
dc.identifier.journalThe Journal of experimental medicineen
refterms.dateFOA2018-06-13T15:33:26Z
html.description.abstractNeutrophil 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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