title: Taxol alleviates 2-methoxyestradiol-induced endothelial permeability.
abstract: We have previously shown that the anti-cancer agent 2-methoxyestradiol (2ME) induces hyperpermeability across endothelial monolayers. Here, we show that both microtubule disruptor, 2ME, and microtubule stabilizer, paclitaxel (taxol), increase vascular lung permeability in vitro and in vivo. Simultaneous application of 2ME and taxol alleviates 2ME-induced endothelial barrier dysfunction, which is evident by the decreased Evans Blue Dye accumulation in lung tissue and increased transendothelial resistance across monolayers. 2ME significantly increases the level of p38 and MLC phosphorylation in both endothelial monolayers and murine lungs; this increase is suppressed in the presence of taxol. Taxol treatment leads to an immediate and sustained increase in tubulin acetylation in human pulmonary artery endothelial cells (HPAEC). Surprisingly, 2ME treatment also increases tubulin acetylation; however, the onset of this process is delayed and coincides with the stage of a partial barrier restoration in HPAEC monolayer. Inhibition of histone deacetylase 6 (HDAC6) with tubacin increases tubulin acetylation level, suppresses 2ME-induced HSP27 and MLC phosphorylation, and decreases 2ME-induced barrier dysfunction, suggesting barrier-protective and/or barrier-restorative role for tubulin acetylation in vascular endothelium.
authors.affiliation: Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Gorshkov
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zemskova
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Verin
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogatcheva
mesh_terms: D000077584:2-Methoxyestradiol; D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000813:Anilides; D055551:HSP27 Heat-Shock Proteins; D006877:Hydroxamic Acids; D018994:Myosin Light Chains; D014404:Tubulin; C474316:tubacin; D004958:Estradiol; D000077584:2-Methoxyestradiol; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; D017239:Paclitaxel
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