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Modulating Endothelial Barrier Function by Targeting Vimentin Phosphorylation
Author(s) -
Liu Tiegang,
Ghamloush Maher M.,
Aldawood Ali,
Warburton Rod,
Toksoz Deniz,
Hill Nicholas S.,
Tang Dale D.,
Kayyali Usamah S.
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24590
Subject(s) - vimentin , phosphorylation , intermediate filament , microbiology and biotechnology , endothelium , intermediate filament protein , biology , cytoskeleton , chemistry , immunology , cell , biochemistry , endocrinology , immunohistochemistry
Vimentin is a major intermediate filament protein in vascular endothelial cells which might be involved in their function as a barrier tissue. It is proposed to dynamically maintain integrity of the endothelium as a tightly regulated permeability barrier that is subjected to a variety of shear and contractile forces. The results described in this report demonstrate that vimentin plays that role through mechanisms that are dependent on its phosphorylation state. Withaferin A (WFA), a vimentin targeting drug is shown to disrupt endothelial barrier function through its effects on vimentin filament distribution and physical properties. These effects are related to WFA's ability to increase vimentin phosphorylation. Through overexpressing a non‐phosphorylatable vimentin mutant we can block the effects of WFA on vimentin distribution and barrier permeability. The barrier augmentation effect appears to extend to endothelial cells that do not express detectable mutant vimentin which might suggest transmissible effects across cells. Blocking vimentin phosphorylation also protects the endothelial barrier against LPS endotoxin, implicating it as a target for drug development against pulmonary edema and acute respiratory distress syndrome (ARDS). J. Cell. Physiol. 229: 1484–1493, 2014. © 2014 Wiley Periodicals, Inc.