RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock

Constantinos M. Mikelis, May Simaan, Koji Ando, Shigetomo Fukuhara, Atsuko Sakurai, Panomwat Amornphimoltham, Andrius Masedunskas, Roberto Weigert, Triantafyllos Chavakis, Ralf H. Adams, Stefan Offermanns, Naoki Mochizuki, Yi Zheng and J. Silvio Gutkind ()
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Constantinos M. Mikelis: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
May Simaan: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Koji Ando: CREST-JST, National Cerebral and Cardiovascular Center Research Institute
Shigetomo Fukuhara: CREST-JST, National Cerebral and Cardiovascular Center Research Institute
Atsuko Sakurai: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Panomwat Amornphimoltham: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Andrius Masedunskas: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Roberto Weigert: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Triantafyllos Chavakis: Faculty of Medicine, Technische Universität Dresden
Ralf H. Adams: Max-Planck Institute for Molecular Biomedicine
Stefan Offermanns: Max-Planck Institute for Heart and Lung Research
Naoki Mochizuki: CREST-JST, National Cerebral and Cardiovascular Center Research Institute
Yi Zheng: Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine
J. Silvio Gutkind: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma and anaphylaxis. Yet, how histamine induces the disruption of the endothelial barrier is not well defined. By using genetically modified animal models, pharmacologic inhibitors and a synthetic biology approach, here we show that the small GTPase RhoA mediates histamine-induced vascular leakage. Histamine causes the rapid formation of focal adherens junctions, disrupting the endothelial barrier by acting on H1R Gαq-coupled receptors, which is blunted in endothelial Gαq/11 KO mice. Interfering with RhoA and ROCK function abolishes endothelial permeability, while phospholipase Cβ plays a limited role. Moreover, endothelial-specific RhoA gene deletion prevents vascular leakage and passive cutaneous anaphylaxis in vivo, and ROCK inhibitors protect from lethal systemic anaphylaxis. This study supports a key role for the RhoA signalling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage.

Date: 2015
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DOI: 10.1038/ncomms7725

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