title: Modulating endothelial barrier function by targeting vimentin phosphorylation.
abstract: 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).
authors.affiliation: Pulmonary & Critical Care Division, Department of Medicine/Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Tiegang
authors.initials: T
authors.lastname: Liu
authors.forename: Maher M
authors.initials: MM
authors.lastname: Ghamloush
authors.forename: Ali
authors.initials: A
authors.lastname: Aldawood
authors.forename: Rod
authors.initials: R
authors.lastname: Warburton
authors.forename: Deniz
authors.initials: D
authors.lastname: Toksoz
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.forename: Dale D
authors.initials: DD
authors.lastname: Tang
authors.forename: Usamah S
authors.initials: US
authors.lastname: Kayyali
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D051381:Rats; D012694:Serine; D012995:Solubility; D013997:Time Factors; D014162:Transfection; D014746:Vimentin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054358:Withanolides / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D014746:Vimentin; D054358:Withanolides; D012694:Serine; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases; C009684:withaferin A