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1 Department of Experimental Immunohematology, Sanquin Research at CLB, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: p.hordijk{at}sanquin.nl.
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-CAMs) 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 crosslinking of VCAM-1 on IL-1-activated primary human umbilical vein endothelial cells induced actin stress fiber formation, contractility and intercellular gaps. The effects induced by VCAM-1 crosslinking 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 to induce intercellular gaps in pHUVEC in a Rho-dependent fashion. Using 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 towards cell-cell junctions was accompanied by, and was 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 VE-cadherin-mediated endothelial cell-cell adhesion and leukocyte extravasation.
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