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RECEPTORS AND SIGNAL TRANSDUCTION
Department of Experimental Immunohematology, Sanquin Research at CLB and Laboratory for Clinical and Experimental Immunology, Academic Medical Center, 1066 CX Amsterdam, The Netherlands
Submitted 4 February 2003 ; accepted in final form 13 April 2003
Leukocyte adhesion is mediated totally and transendothelial migration
partially by heterotypic interactions between the 
1- and
2-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-1-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.
human umbilical vein endothelial cells; vascular-endothelial cadherin; F-actin; reactive oxygen species; p38 mitogen-activated protein kinase; vascular cell adhesion molecule
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