Faculty Collaboration Database

Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. J Biol Chem 2007 Aug 17;282(33):23910-8

Date

06/15/2007

Pubmed ID

17562701

DOI

10.1074/jbc.M702169200

Scopus ID

2-s2.0-34447627607 (requires institutional sign-in at Scopus site)   162 Citations

Abstract

Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, but the mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize the cytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of the endothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either part of this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting that coordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, a GTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1 treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletal and pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190 RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-induced pulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascular permeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on the Rho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical to the protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence that targeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threatening endotoxemic conditions such as sepsis and acute respiratory distress syndrome.

Author List

Mammoto T, Parikh SM, Mammoto A, Gallagher D, Chan B, Mostoslavsky G, Ingber DE, Sukhatme VP

Authors

Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiopoietin-1
Animals
Capillary Permeability
Cells, Cultured
Endothelium, Vascular
GTPase-Activating Proteins
Humans
Mice
Phosphorylation
Receptor, TIE-2
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein