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- Title
Opposing Effects of the Angiopoietins on the Thrombin- Induced Permeability of Human Pulmonary Microvascular Endothelial Cells.
- Authors
der Heijden, Melanie van; Nieuw Amerongen, Geerten P. van; Bezu, Jan van; Paul, Marinus A.; Johan Groeneveld, A. B.; van Hinsbergh, Victor W. M.
- Abstract
Background: Angiopoietin-2 (Ang-2) is associated with lung injury in ALI/ARDS. As endothelial activation by thrombin plays a role in the permeability of acute lung injury and Ang-2 may modulate the kinetics of thrombin-induced permeability by impairing the organization of vascular endothelial (VE-)cadherin, and affecting small Rho GTPases in human pulmonary microvascular endothelial cells (HPMVECs), we hypothesized that Ang-2 acts as a sensitizer of thrombin-induced hyperpermeability of HPMVECs, opposed by Ang-1. Methodology/Principal Findings: Permeability was assessed by measuring macromolecule passage and transendothelial electrical resistance (TEER). Angiopoietins did not affect basal permeability. Nevertheless, they had opposing effects on the thrombin-induced permeability, in particular in the initial phase. Ang-2 enhanced the initial permeability increase (passage, P = 0.010; TEER, P = 0.021) in parallel with impairment of VE-cadherin organization without affecting VE-cadherin Tyr685 phosphorylation or increasing RhoA activity. Ang-2 also increased intercellular gap formation. Ang-1 preincubation increased Rac1 activity, enforced the VE-cadherin organization, reduced the initial thrombin-induced permeability (TEER, P = 0.027), while Rac1 activity simultaneously normalized, and reduced RhoA activity at 15 min thrombin exposure (P = 0.039), but not at earlier time points. The simultaneous presence of Ang-2 largely prevented the effect of Ang-1 on TEER and macromolecule passage. Conclusions/Significance: Ang-1 attenuated thrombin-induced permeability, which involved initial Rac1 activationenforced cell-cell junctions, and later RhoA inhibition. In addition to antagonizing Ang-1, Ang-2 had also a direct effect itself. Ang-2 sensitized the initial thrombin-induced permeability accompanied by destabilization of VE-cadherin junctions and increased gap formation, in the absence of increased RhoA activity.
- Subjects
ANGIOPOIETINS; THROMBIN; PERMEABILITY; CELLULAR mechanics; ENDOTHELIUM; PHOSPHORYLATION; LUNG injuries; CADHERINS
- Publication
PLoS ONE, 2011, Vol 6, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0023448