Mikelis Constantinos M, Simaan May, Ando Koji, Fukuhara Shigetomo, Sakurai Atsuko, Amornphimoltham Panomwat, Masedunskas Andrius, Weigert Roberto, Chavakis Triantafyllos, Adams Ralf H, Offermanns Stefan, Mochizuki Naoki, Zheng Yi, Gutkind J Silvio
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Department of Cell Biology, CREST-JST, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Nat Commun. 2015 Apr 10;6:6725. doi: 10.1038/ncomms7725.
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.
组胺诱导的血管渗漏是许多高发性人类疾病（包括过敏、哮喘和过敏反应）的一个重要组成部分。然而，组胺如何诱导内皮屏障的破坏尚不清楚。通过使用基因改造动物模型、药理学抑制剂和合成生物学方法，我们在此表明小GTP酶RhoA介导组胺诱导的血管渗漏。组胺通过作用于H1R Gαq偶联受体导致粘着斑的快速形成，破坏内皮屏障，这在内皮Gαq/11基因敲除小鼠中减弱。干扰RhoA和ROCK功能可消除内皮通透性，而磷脂酶Cβ的作用有限。此外，内皮特异性RhoA基因缺失可预防体内血管渗漏和被动皮肤过敏反应，ROCK抑制剂可预防致死性全身性过敏反应。这项研究支持RhoA信号通路在血管通透性中的关键作用，从而为许多以异常血管渗漏为特征的人类疾病确定了新的药理学靶点。
