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(Circulation Research. 2007;101:50.)
© 2007 American Heart Association, Inc.

Molecular Medicine

RhoGDI-1 Modulation of the Activity of Monomeric RhoGTPase RhoA Regulates Endothelial Barrier Function in Mouse Lungs

Matvey Gorovoy^*, Radu Neamu^*, Jiaxin Niu, Stephen Vogel, Dan Predescu, Jun Miyoshi, Yoshimi Takai, Vidisha Kini, Dolly Mehta, Asrar B. Malik, Tatyana Voyno-Yasenetskaya

From the Department of Pharmacology (M.G., R.N., J.N., S.V., D.P., V.K., D.M., A.B.M., T.V.-Y.), University of Illinois College of Medicine and Center for Lung and Vascular Biology, Chicago; the Department of Molecular Biology (J.M.), Osaka Medical Center for Cancer and Cardiovascular Diseases, and the Department of Molecular Biology and Biochemistry (Y.T.), Osaka University School of Medicine, Osaka, Japan.

Correspondence to Dr T. Voyno-Yasenetskaya, University of Illinois, Department of Pharmacology (MC 868), 835 S. Wolcott Ave, Chicago, IL 60612. E-mail tvy{at}uic.edu

Rho family GTPases have been implicated in the regulation of endothelial permeability via their actions on actin cytoskeletal organization and integrity of interendothelial junctions. In cell culture studies, activation of RhoA disrupts interendothelial junctions and increases endothelial permeability, whereas activation of Rac1 and Cdc42 enhances endothelial barrier function by promoting the formation of restrictive junctions. The primary regulators of Rho proteins, guanine nucleotide dissociation inhibitors (GDIs), form a complex with the GDP-bound form of the Rho family of monomeric G proteins, and thus may serve as a nodal point regulating the activation state of RhoGTPases. In the present study, we addressed the in vivo role of RhoGDI-1 in regulating pulmonary microvascular permeability using RhoGDI-1^–/– mice. We observed that basal endothelial permeability in lungs of RhoGDI-1^–/– mice was 2-fold greater than wild-type mice. This was the result of opening of interendothelial junctions in lung microvessels which are normally sealed. The activity of RhoA (but not of Rac1 or Cdc42) was significantly increased in RhoGDI-1^–/– lungs as well as in cultured endothelial cells on downregulation of RhoGDI-1 with siRNA, consistent with RhoGDI-1–mediated modulation RhoA activity. Thus, RhoGDI-1 by repressing RhoA activity regulates lung microvessel endothelial barrier function in vivo. In this regard, therapies augmenting endothelial RhoGDI-1 function may be beneficial in reestablishing the endothelial barrier and lung fluid balance in lung inflammatory diseases such as acute respiratory distress syndrome.

Key Words: RhoGDI • Rho GTPase • endothelial permeability • lung perfusion

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