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VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration

Sandra van Wetering1, Nadia van den Berk, Jaap D van Buul

  • 1Department of Experimental Immunohematology, Sanquin Research at CLB, 1066 CX Amsterdam, The Netherlands.

American Journal of Physiology. Cell Physiology
|April 18, 2003
PubMed

Insights

Vascular Cell Adhesion Molecule-1 (VCAM-1) signaling controls endothelial cell-cell adhesion and leukocyte migration. Rac-dependent signaling pathways involving reactive oxygen species and p38 MAPK are crucial for VCAM-1

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Leukocyte adhesion and migration involve interactions between leukocyte integrins and endothelial Ig-like cell adhesion molecules (Ig-CAMs).
  • VCAM-1 and ICAM-1 are key endothelial ligands involved in these processes.
  • Both integrins and Ig-CAMs possess signaling capabilities influencing cellular behavior.

Purpose of the Study:

  • To investigate the role of VCAM-1-mediated signaling in regulating endothelial cell-cell adhesion.
  • To determine the involvement of VCAM-1 signaling in leukocyte transendothelial migration.

Main Methods:

  • Antibody-mediated cross-linking of VCAM-1 on activated human umbilical vein endothelial cells (pHUVEC).
  • Inhibition studies using C3 toxin and a cell-permeable peptide inhibitor.
  • Analysis of small GTPase (Rho, Rac) activation, actin stress fiber formation, and intercellular gap dynamics.
  • Measurement of reactive oxygen species production and p38 MAPK activation.
  • Assessment of monocytic U937 cell transendothelial migration.

Main Results:

  • VCAM-1 cross-linking induced actin stress fibers, contractility, and intercellular gaps in pHUVEC.
  • These effects were Rho-dependent and accompanied by Rac activation.
  • Rac signaling was essential for VCAM-1-mediated loss of endothelial cell-cell adhesion.
  • VCAM-1 signaling involved Rac-dependent reactive oxygen species production and p38 MAPK activation.
  • Inhibition of Rac signaling blocked U937 cell transendothelial migration.

Conclusions:

  • VCAM-1-induced signaling, particularly Rac-dependent pathways, modulates endothelial cell-cell adhesion.
  • VCAM-1 signaling plays a critical role in leukocyte extravasation through the endothelium.
  • Understanding these pathways offers insights into inflammatory responses and immune cell trafficking.

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