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

被引:71
作者
Collins, NT
Cummins, PM [1 ]
Colgan, OC
Ferguson, G
Birney, YA
Murphy, RP
Meade, G
Cahill, PA
机构
[1] Dublin City Univ, Vasc Hlth Res Ctr, Fac Sci & Hlth, Dublin 9, Ireland
[2] Royal Coll Surgeons Ireland, Dept Clin Pharmacol, Imaging Facil, Dublin 2, Ireland
关键词
occludin; ZO-1; endothelium; cyclic strain; permeability;
D O I
10.1161/01.ATV.0000194097.92824.b3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:62 / 68
页数:7
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