title: VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration.
abstract: Leukocyte adhesion is mediated totally and transendothelial migration partially by heterotypic interactions between the beta1- and beta2-integrins on the leukocytes and their ligands, Ig-like cell adhesion molecules (Ig-CAM), VCAM-1, and ICAM-1, on the endothelium. Both integrins and Ig-CAMs are known to have signaling capacities. In this study we analyzed the role of VCAM-1-mediated signaling in the control of endothelial cell-cell adhesion and leukocyte transendothelial migration. Antibody-mediated cross-linking of VCAM-1 on IL-1beta-activated primary human umbilical vein endothelial cells (pHUVEC) induced actin stress fiber formation, contractility, and intercellular gaps. The effects induced by VCAM-1 cross-linking were inhibited by C3 toxin, indicating that the small GTPase p21Rho is involved. In addition, the effects of VCAM-1 were accompanied by activation of Rac, which we recently showed induce intercellular gaps in pHUVEC in a Rho-dependent fashion. With the use of a cell-permeable peptide inhibitor, it was shown that Rac signaling is required for VCAM-1-mediated loss of cell-cell adhesion. Furthermore, VCAM-1-mediated signaling toward cell-cell junctions was accompanied by, and dependent on, Rac-mediated production of reactive oxygen species and activation of p38 MAPK. In addition, it was found that inhibition of Rac-mediated signaling blocks transendothelial migration of monocytic U937 cells. Together, these data indicate that VCAM-1-induced, Rac-dependent signaling plays a key role in the modulation of vascular-endothelial cadherin-mediated endothelial cell-cell adhesion and leukocyte extravasation.
authors.affiliation: Department of Experimental Immunohematology, Sanquin Research at CLB, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: van Wetering
authors.forename: Nadia
authors.initials: N
authors.lastname: van den Berk
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Frederik P J
authors.initials: FP
authors.lastname: Mul
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lommerse
authors.forename: Rogier
authors.initials: R
authors.lastname: Mous
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: ten Klooster
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D001905:Botulinum Toxins / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001905:Botulinum Toxins; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein