| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
British Heart Foundation Laboratories, Department of Medicine, University College London; and Institute of Child Health, London, United Kingdom
Submitted 24 September 2004 ; accepted in final form 2 December 2004
Hypoxia/reoxygenation-induced changes in endothelial permeability are accompanied by endothelial actin cytoskeletal and adherens junction remodeling, but the mechanisms involved are uncertain. We therefore measured the activities of the Rho GTPases Rac1, RhoA, and Cdc42 during hypoxia/reoxygenation and correlated them with changes in endothelial permeability, remodeling of the actin cytoskeleton and adherens junctions, and production of ROS. Dominant negative forms of Rho GTPases were introduced into cells by adenoviral gene transfer and transfection, and inhibitors of NADPH oxidase, PI3 kinase, and Rho kinase were used to characterize the signaling pathways involved. In some experiments constitutively activated forms of RhoA and Rac1 were also used. We show for the first time that hypoxia/reoxygenation-induced changes in endothelial permeability result from coordinated actions of the Rho GTPases Rac1 and RhoA. Rac1 and RhoA rapidly respond to changes in oxygen tension, and their activity depends on NADPH oxidase- and PI3 kinase-dependent production of ROS. Rac1 acts upstream of RhoA, and its transient inhibition by acute hypoxia leads to activation of RhoA followed by stress fiber formation, dispersion of adherens junctions, and increased endothelial permeability. Reoxygenation strongly activates Rac1 and restores cortical localization of F-actin and VE-cadherin. This effect is a result of Rac1-mediated inhibition of RhoA and can be prevented by activators of RhoA, L63RhoA, and lysophosphatidic acid. Cdc42 activation follows the RhoA pattern of activation but has no effect on actin remodeling, junctional integrity, or endothelial permeability. Our results show that Rho GTPases act as mediators coupling cellular redox state to endothelial function.
reactive oxygen species; adherens junctions; actin cytoskeleton
This article has been cited by other articles:
|
|
 |
|
  N. Schlegel and J. Waschke VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells Am J Physiol Cell Physiol, March 1, 2009; 296(3): C453 - C462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Ganter, J. Roux, G. Su, S. V. Lynch, C. S. Deutschman, Y. G. Weiss, S. C. Christiaans, B. Myazawa, E. Kipnis, J. P. Wiener-Kronish, et al. Role of Small GTPases and {alpha}v{beta}5 Integrin in Pseudomonas aeruginosa-Induced Increase in Lung Endothelial Permeability Am. J. Respir. Cell Mol. Biol., January 1, 2009; 40(1): 108 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wojciak-Stothard, B. Torondel, L. Zhao, T. Renne, and J. M. Leiper Modulation of Rac1 Activity by ADMA/DDAH Regulates Pulmonary Endothelial Barrier Function Mol. Biol. Cell, January 1, 2009; 20(1): 33 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B Wojciak-Stothard New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Solodushko, J. C. Parker, and B. Fouty Pulmonary Microvascular Endothelial Cells Form a Tighter Monolayer when Grown in Chronic Hypoxia Am. J. Respir. Cell Mol. Biol., April 1, 2008; 38(4): 491 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Hemnes, A. Zaiman, and H. C. Champion PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L24 - L33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Schlegel, S. Burger, N. Golenhofen, U. Walter, D. Drenckhahn, and J. Waschke The role of VASP in regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization Am J Physiol Cell Physiol, January 1, 2008; 294(1): C178 - C188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nakhaei-Nejad, A. M. Hussain, Q.-X. Zhang, and A. G. Murray Endothelial PI 3-kinase activity regulates lymphocyte diapedesis Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3608 - H3616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lorenowicz, M. Fernandez-Borja, A.-M. D. van Stalborch, M. A. J. A. van Sterkenburg, P. S. Hiemstra, and P. L. Hordijk Microtubule dynamics and Rac-1 signaling independently regulate barrier function in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1321 - L1331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wojciak-Stothard, B. Torondel, L. Y. F. Tsang, I. Fleming, B. Fisslthaler, J. M. Leiper, and P. Vallance The ADMA/DDAH pathway is a critical regulator of endothelial cell motility J. Cell Sci., March 15, 2007; 120(6): 929 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Weir and S. L. Archer COUNTERPOINT: HYPOXIC PULMONARY VASOCONSTRICTION IS NOT MEDIATED BY INCREASED PRODUCTION OF REACTIVE OXYGEN SPECIES J Appl Physiol, September 1, 2006; 101(3): 995 - 998. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moldovan, K. Mythreye, P. J. Goldschmidt-Clermont, and L. L. Satterwhite Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1 Cardiovasc Res, July 15, 2006; 71(2): 236 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Wojciak-Stothard, L. Y. F. Tsang, E. Paleolog, S. M. Hall, and S. G. Haworth Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1173 - L1182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Moldobaeva, L. E. Welsh-Servinsky, L. A. Shimoda, R. S. Stephens, A. D. Verin, R. M. Tuder, and D. B. Pearse Role of protein kinase G in barrier-protective effects of cGMP in human pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L919 - L930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Stamatovic, O. B. Dimitrijevic, R. F. Keep, and A. V. Andjelkovic Protein Kinase C{alpha}-RhoA Cross-talk in CCL2-induced Alterations in Brain Endothelial Permeability J. Biol. Chem., March 31, 2006; 281(13): 8379 - 8388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ogawa, H. Wada, N. Okada, I. Harada, T. Nakajima, E. B. Pasquale, and S. Tsuyama EphB2 and ephrin-B1 expressed in the adult kidney regulate the cytoarchitecture of medullary tubule cells through Rho family GTPases J. Cell Sci., February 1, 2006; 119(3): 559 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Skuli, S. Monferran, C. Delmas, I. Lajoie-Mazenc, G. Favre, C. Toulas, and E. Cohen-Jonathan-Moyal Activation of RhoB by Hypoxia Controls Hypoxia-Inducible Factor-1{alpha} Stabilization through Glycogen Synthase Kinase-3 in U87 Glioblastoma Cells Cancer Res., January 1, 2006; 66(1): 482 - 489. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
