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Regulation of vimentin intermediate filaments in endothelial cells by hypoxia.

Abstract
Hypoxia triggers responses in endothelial cells that play roles in many conditions including high-altitude pulmonary edema and tumor angiogenesis. Signaling pathways activated by hypoxia modify cytoskeletal and contractile proteins and alter the biomechanical properties of endothelial cells. Intermediate filaments are major components of the cytoskeleton whose contribution to endothelial physiology is not well understood. We have previously shown that hypoxia-activated signaling in endothelial cells alters their contractility and adhesiveness. We have also linked p38-MAP kinase signaling pathway leading to HSP27 phosphorylation and increased actin stress fiber formation to endothelial barrier augmentation. We now show that vimentin, a major intermediate filament protein in endothelial cells, is regulated by hypoxia. Our results indicate that exposure of endothelial cells to hypoxia causes vimentin filament networks to initially redistribute perinuclearly. However, by 1 hour hypoxia these networks reform and appear more continuous across cells than under normoxia. Hypoxia also causes transient changes in vimentin phosphorylation, and activation of PAK1, a kinase that regulates vimentin filament assembly. In addition, exposure to 1 hour hypoxia increases the ratio of insoluble/soluble vimentin. Overexpression of phosphomimicking mutant HSP27 (pmHSP27) causes changes in vimentin distribution that are similar to those observed in hypoxic cells. Knocking-down HSP27 destroys the vimentin filamentous network, and disrupting vimentin filaments with acrylamide increases endothelial permeability. Both hypoxia- and pmHSP27 overexpression-induced changes are reversed by inhibition of phosphatase activity. In conclusion hypoxia causes redistribution of vimentin to a more insoluble and extensive filamentous network that could play a role in endothelial barrier stabilization. Vimentin redistribution appears to be mediated through altering the phosphorylation of the protein and its interaction with HSP27.
AuthorsTiegang Liu, Oscar E Guevara, Rod R Warburton, Nicholas S Hill, Matthias Gaestel, Usamah S Kayyali
JournalAmerican journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 299 Issue 2 Pg. C363-73 (Aug 2010) ISSN: 1522-1563 [Electronic] United States
PMID20427712 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • HSP27 Heat-Shock Proteins
  • Vimentin
Topics
  • Animals
  • Cell Hypoxia (physiology)
  • Cells, Cultured
  • Endothelial Cells (metabolism, physiology)
  • Gene Knockdown Techniques
  • HSP27 Heat-Shock Proteins (deficiency, genetics)
  • Intermediate Filaments (physiology)
  • Phosphorylation (physiology)
  • Rats
  • Vimentin (metabolism, physiology)

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