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 signaling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage.
Highlights
Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma and anaphylaxis
The emerging picture is that VEGF acts by a biochemical route that involves the sequential activation of VEGFR2 and the tyrosine kinase Src, and the concomitant tyrosine phosphorylation of VE-cadherin and the stimulation of a signalling pathway resulting in the activation of the small GTPase Rac[1]
Our findings support a model whereby histamine and other permeability factors acting on Gaq-coupled G protein-coupled receptors (GPCRs) promote the activation of PLCb and the rapid mobilization of calcium on endothelial cells, while a distinct Gaq downstream target, Trio, initiates the activation of RhoA and the consequent stimulation of ROCK (Fig. 5)
Summary
Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma and anaphylaxis. Increase in vascular permeability occurs under many physiological conditions, including wound repair, inflammation and thrombotic reactions, while disturbed adherens junctions is a characteristic of pathological conditions involving vascular leakage and inflammation[2,6] These include many human diseases, such as tumour-induced angiogenesis, ocular diseases and anaphylactic and septic shock, which has prompted the growing interest in understanding the molecular mechanisms underlying aberrant vascular leakiness in disease. We show that histamine stimulates a Rho GEF, Trio, acting downstream from Gaq, which in turn promotes the activation of RhoA and its regulated signalling circuitry, including the serine-threonine kinase ROCK. This results in the formation of focal adherens junctions (FAJs) and the disruption of the endothelial barrier. We provide evidence that RhoA activation is required for vascular permeability caused by histamine and other permeability factors released upon mast cell degranulation, and that inhibition of RhoA or its downstream target, ROCK, may represent suitable targets for pharmacological intervention in multiple disease conditions that involve aberrant vascular leakage
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