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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 β 1- and β 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-1β-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.
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“VCAM1 is known for leukocyte-endothelial cell adhesion via interaction with integrins and activates calcium release and RAC1 activation (40).”
From Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway (2023) · cites this paper as [40]
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Metadata
- Authors
- van Wetering, S., van den Berk, N., van Buul, J. D., Mul, F. P. J., Lommerse, I., Mous, R., Klooster, J.-P. T., Zwaginga, J.-J., & Hordijk, P. L.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2003-08
- Volume
- 285
- Issue
- 2
- Pages
- C343-C352
- ISSN
- 0363-6143
- 1522-1563
- Cited by
- 185
- References
- 0
- Language
- en
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