title: RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock.
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.
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Constantinos M
authors: CM
authors: Mikelis
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: May
authors: M
authors: Simaan
authors: Department of Cell Biology, CREST-JST, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Koji
authors: K
authors: Ando
authors: Department of Cell Biology, CREST-JST, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Shigetomo
authors: S
authors: Fukuhara
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Atsuko
authors: A
authors: Sakurai
authors: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Panomwat
authors: P
authors: Amornphimoltham
authors: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Andrius
authors: A
authors: Masedunskas
authors: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Roberto
authors: R
authors: Weigert
authors: Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Dresden 01307, Germany.
authors: Triantafyllos
authors: T
authors: Chavakis
authors: 1] Department of Tissue Morphogenesis, Max-Planck Institute for Molecular Biomedicine, Münster D-48149, Germany [2] Faculty of Medicine, University of Münster, Münster 48149, Germany.
authors: Ralf H
authors: 0000000330317677
authors: RH
authors: Adams
authors: Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors: Stefan
authors: S
authors: Offermanns
authors: Department of Cell Biology, CREST-JST, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Naoki
authors: N
authors: Mochizuki
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors: Yi
authors: Y
authors: Zheng
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: J Silvio
authors: JS
authors: Gutkind
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000577:Amides / Q000494:pharmacology; D000707:Anaphylaxis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: D000577:Amides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D011969:Receptors, Histamine H1; C108830:Y 27632; D006632:Histamine; D054460:rho-Associated Kinases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020742:rhoA GTP-Binding Protein