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

Author

Listed:
  • 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
    Faculty of Medicine, University of Münster)

  • 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)

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.

Suggested Citation

  • Constantinos M. Mikelis & May Simaan & Koji Ando & Shigetomo Fukuhara & Atsuko Sakurai & Panomwat Amornphimoltham & Andrius Masedunskas & Roberto Weigert & Triantafyllos Chavakis & Ralf H. Adams & Ste, 2015. "RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7725
    DOI: 10.1038/ncomms7725
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