Novel role of microtubules in thrombin‐induced endothelial barrier dysfunction
Open Access
- 1 December 2004
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 18 (15), 1879-1890
- https://doi.org/10.1096/fj.04-2328com
Abstract
Disturbances in endothelial cell (EC) barrier regulation are critically dependent upon rearrangements of EC actin cytoskeleton. However, the role of microtubule (MT) network in the regulation of EC permeability is not well understood. We examined involvement of MT remodeling in thrombin-induced EC permeability and explored MT regulation by heterotrimeric G12/13 proteins and by small GTPase Rho. Thrombin induced phosphorylation of MT regulatory protein tau at Ser409 and Ser262 and peripheral MT disassembly, which was linked to increased EC permeability. MT stabilization by taxol attenuated thrombin- induced permeability, actin remodeling, and paracellular gap formation and diminished thrombin-induced activation of Rho and Rho-kinase. Expression of activated Gα12/13 subunits involved in thrombin-mediated signaling or their effector p115RhoGEF involved in Rho activation caused MT disassembly, whereas p115RhoGEF-specific negative regulator RGS preserved MT from thrombin-induced disassembly. Consistent with these results, expression of activated RhoA and Rho-kinase induced MT disassembly. Conversely, thrombin-induced disassembly of peripheral MT network was attenuated by expression of dominant negative RhoA and Rho-kinase mutants or by pharmacological inhibition of Rho-kinase. Collectively, our data demonstrate for the first time a critical involvement of MT disassembly in thrombin-induced EC barrier dysfunction and indicate G-protein-dependent mechanisms of thrombin-induced MT alteration.—Birukova, A. A., Birukov, K G., Smurova, K., Adyshev, D., Kaibuchi, K., Alieva, I., Garcia, J. G. N., Verin, A. D. Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB J. 18, 1879-1890 (2004)Keywords
This publication has 53 references indexed in Scilit:
- Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: Role of Rho‐dependent mechanismsJournal of Cellular Physiology, 2004
- Microfilaments and microtubules maintain endothelial integrityMicroscopy Research and Technique, 2002
- Vascular pharmacology of acute lung injury and acute respiratory distress syndromeVascular Pharmacology, 2002
- Microtubule disassembly increases endothelial cell barrier dysfunction: role of MLC phosphorylationAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2001
- Activation of RhoA by Thrombin in Endothelial HyperpermeabilityCirculation Research, 2000
- Functional cooperation between the microtubule and actin cytoskeletonsCurrent Opinion in Cell Biology, 2000
- Positive feedback interactions between microtubule and actin dynamics during cell motilityCurrent Opinion in Cell Biology, 1999
- Regulation of Thrombin-Mediated Endothelial Cell Contraction and PermeabilitySeminars in Thrombosis and Hemostasis, 1996
- Mechanisms of increased endothelial permeabilityCanadian Journal of Physiology and Pharmacology, 1996
- Regulation of endothelial cell gap formation and barrier dysfunction: Role of myosin light chain phosphorylationJournal of Cellular Physiology, 1995