Cyclic strain-mediated regulation of vascular endothelial occludin and ZO-1: influence on intercellular tight junction assembly and function

Nora T Collins, Philip M Cummins, Olga C Colgan, Gail Ferguson, Yvonne A Birney, Ronan P Murphy, Gerardene Meade, Paul A Cahill

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

OBJECTIVE: The vascular endothelium constitutes a highly effective fluid/solute barrier through the regulated apposition of intercellular tight junction complexes. Because endothelium-mediated functions and pathology are driven by hemodynamic forces (cyclic strain and shear stress), we hypothesized a dynamic regulatory link between endothelial tight junction assembly/function and hemodynamic stimuli. We, therefore, examined the effects of cyclic strain on the expression, modification, and function of 2 pivotal endothelial tight junction components, occludin and ZO-1.

METHODS AND RESULTS: For these studies, bovine aortic endothelial cells were subjected to physiological levels of equibiaxial cyclic strain (5% strain, 60 cycles/min, 24 hours). In response to strain, both occludin and ZO-1 protein expression increased by 2.3+/-0.1-fold and 2.0+/-0.3-fold, respectively, concomitant with a strain-dependent increase in occludin (but not ZO-1) mRNA levels. These changes were accompanied by reduced occludin tyrosine phosphorylation (75.7+/-8%) and increased ZO-1 serine/threonine phosphorylation (51.7+/-9% and 82.7+/-25%, respectively), modifications that could be completely blocked with tyrosine phosphatase and protein kinase C inhibitors (dephostatin and rottlerin, respectively). In addition, there was a significant strain-dependent increase in endothelial occludin/ZO-1 association (2.0+/-0.1-fold) in parallel with increased localization of both occludin and ZO-1 to the cell-cell border. These events could be completely blocked by dephostatin and rottlerin, and they correlated with a strain-dependent reduction in transendothelial permeability to FITC-dextran.

CONCLUSIONS: Overall, these findings indicate that cyclic strain modulates both the expression and phosphorylation state of occludin and ZO-1 in vascular endothelial cells, with putative consequences for endothelial tight junction assembly and barrier integrity.

Original languageEnglish
Pages (from-to)62-8
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number1
DOIs
Publication statusPublished - Jan 2006

Keywords

  • Acetophenones/pharmacology
  • Animals
  • Aorta/cytology
  • Benzopyrans/pharmacology
  • Capillary Permeability/physiology
  • Cattle
  • Dextrans/pharmacokinetics
  • Endothelial Cells/cytology
  • Enzyme Inhibitors/pharmacology
  • Fluorescein-5-isothiocyanate/analogs & derivatives
  • Gene Expression/physiology
  • Hydroquinones/pharmacology
  • In Vitro Techniques
  • Membrane Proteins/genetics
  • Occludin
  • Phosphoproteins/genetics
  • Phosphorylation
  • Protein Kinase C/antagonists & inhibitors
  • Protein Tyrosine Phosphatases/antagonists & inhibitors
  • RNA, Messenger/metabolism
  • Stress, Mechanical
  • Tight Junctions/metabolism
  • Zonula Occludens-1 Protein

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