Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo.

2.50
HDL Handle:
http://hdl.handle.net/10033/209453
Title:
Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo.
Authors:
Schnoor, Michael; Lai, Frank P L; Zarbock, Alexander; Kläver, Ruth; Polaschegg, Christian; Schulte, Dörte; Weich, Herbert A; Oelkers, J Margit; Rottner, Klemens; Vestweber, Dietmar
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.
Affiliation:
Max Planck Institute for Molecular Biomedicine, D 48149 Münster, Germany.
Citation:
Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. 2011, 208 (8):1721-35 J. Exp. Med.
Journal:
The Journal of experimental medicine
Issue Date:
1-Aug-2011
URI:
http://hdl.handle.net/10033/209453
DOI:
10.1084/jem.20101920
PubMed ID:
21788407
Type:
Article
Language:
en
ISSN:
1540-9538
Appears in Collections:
Publications of RG Cytoskeleton Dynamics (CYD)

Full metadata record

DC FieldValueLanguage
dc.contributor.authorSchnoor, Michaelen
dc.contributor.authorLai, Frank P Len
dc.contributor.authorZarbock, Alexanderen
dc.contributor.authorKläver, Ruthen
dc.contributor.authorPolaschegg, Christianen
dc.contributor.authorSchulte, Dörteen
dc.contributor.authorWeich, Herbert Aen
dc.contributor.authorOelkers, J Margiten
dc.contributor.authorRottner, Klemensen
dc.contributor.authorVestweber, Dietmaren
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.en
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

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