title: Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo.
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.
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D 48149 Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnoor
authors.forename: Frank P L
authors.initials: FP
authors.lastname: Lai
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Ruth
authors.initials: R
authors.lastname: Kläver
authors.forename: Christian
authors.initials: C
authors.lastname: Polaschegg
authors.forename: Dörte
authors.initials: D
authors.lastname: Schulte
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Weich
authors.forename: J Margit
authors.initials: JM
authors.lastname: Oelkers
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000276:immunology*; D002448:Cell Adhesion / Q000502:physiology; D051356:Cortactin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D014471:Umbilical Veins / Q000166:cytology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins
chemical_list: D000199:Actins; D051356:Cortactin; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009841:Oligonucleotides; D034741:RNA, Small Interfering; C489577:Rhog protein, mouse; D018799:Intercellular Adhesion Molecule-1; D020558:GTP Phosphohydrolases; D020827:rap1 GTP-Binding Proteins; D020741:rho GTP-Binding Proteins