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Thromb Haemost 2014; 112(06): 1088-1102
DOI: 10.1160/th14-04-0299
Review Article
Schattauer GmbH

TNF-induced endothelial barrier disruption: beyond actin and Rho

Beatriz Marcos-Ramiro   *
1   Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
,
Diego García-Weber   *
1   Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
,
Jaime Millán
1   Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
› Author Affiliations
Further Information

Publication History

Received: 01 April 2014

Accepted after minor revision: 16 June 2014

Publication Date:
20 November 2017 (online)

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Summary

The decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of endothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tumour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. However, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that additional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothelial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk between leukocyte transendothelial migration and endothelial permeability during inflammation.

Keywords

Endothelial barrier function - permeability - adhesion - transendothelial migration - Rho - Rac - Cdc42 - ROCK - reactive oxygen species - Src - Fyn - actin - VE-cadherin - ICAM-1 - VCAM-1 - JAM - PECAM-1 - SHP phosphatases - metalloproteases

* Equal contribution.


 

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