on November 3, 2005
Published online before print November 3, 2005, doi: 10.1161/01.ATV.0000194097.92824.b3
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Submitted on July 1, 2005
Accepted on October 20, 2005
Cyclic Strain-Mediated Regulation of Vascular Endothelial Occludin and ZO-1. Influence on Intercellular Tight Junction Assembly and Function
Nora T. Collins ;
From the Vascular Health Research Centre (N.T.C., P.M.C., O.C.C., G.F., Y.A.B., R.P.M., P.A.C.), Faculty of Science and Health, Dublin City University, Glasnevin, and the Department of Clinical Pharmacology Imaging Facility (G.M.), Royal College of Surgeons in Ireland, Dublin, Ireland.
* To whom correspondence should be addressed. E-mail: phil.cummins{at}dcu.ie.
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.
Key words: occludin • ZO-1 • endothelium • cyclic strain • permeability
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