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J. Cell Sci. 116 (22): 4615-4628


Research Article

Potential role of MCP-1 in endothelial cell tight junction `opening': signaling via Rho and Rho kinase

Svetlana M. Stamatovic1, Richard F. Keep1,3, Steven L. Kunkel2, and Anuska V. Andjelkovic1,2,*

1 Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3 Department of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

* Author for correspondence (e-mail: anuskaa{at}umich.edu)

Accepted for publication 8 July 2003.

Abstract: The expression of the monocyte chemoattractant protein-1 (MCP-1) receptor CCR2 by brain endothelial cells suggests that MCP-1 may have other functions than purely driving leukocyte migration into brain parenchyma during inflammation. This study examines one of these potential novel roles of MCP-1 regulation of endothelial permeability using primary cultures of mouse brain endothelial cells. MCP-1 induces reorganization of actin cytoskeleton (stress fiber formation) and redistribution of tight junction proteins, ZO-1, ZO-2 occludin and claudin-5, from the Triton X-100-soluble to the Triton X-100-insoluble fractions. These morphological changes are associated with a decrease in transendothelial electrical membrane resistance and an increase in [14C]inulin permeability. MCP-1 did not induce these events in brain endothelial cells prepared from mice genotype CCR2–/–. The Rho kinase inhibitor Y27632 and inhibition of Rho (C3 exoenzyme, and dominant negative mutant of Rho, RhoT19N) prevented MCP-1-induced stress fiber assembly, reorganization of tight junction proteins and alterations in endothelial permeability. In all, this suggests that a small GTPase Rho and Rho kinase have a pivotal role in MCP-1-induced junction disarrangement. These data are the first to strongly suggest that MCP-1, via CCR2 present on brain endothelial cells, contributes to increased brain endothelial permeability.

Key Words: MCP-1 • Tight junction • RhoA • Rho kinase • Brain endothelial permeability


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