Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport
Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport
复制标题
DOI：
10.1096/fj.08-113274
复制
发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Funk, Colin D.
中科院分区：
文献类型：
--
作者：
Moos, Michael P. W.;Mewburn, Jeffrey D.;Funk, Colin D.
半胱氨酰白三烯（CysLTs）是由5-脂氧合酶（5-LO）、5-LO活化蛋白（FLAP）、白三烯C4合酶和其它下游酶协同作用合成的有效炎症介质，起始于花生四烯酸底物。由巨噬细胞、嗜酸性粒细胞、肥大细胞和其他炎性细胞产生的CysLT激活3种不同的高亲和力CysLT受体：CysLT 1 R、CysLT 2 R和GPR 17。我们试图研究CysLT 2 R表达的血管部位以及该受体在介导血管通透性事件中的作用和机制。在新型CysLT 2 R缺陷型LacZ小鼠模型中，通过报告基因表达研究CysLT 2 R的血管表达。CysLT 2 R在小鼠脑、膀胱、皮肤和提睾肌的小血管中表达，但在大血管中不表达。除了共聚焦显微镜和电子显微镜外，在提睾肌毛细血管后小静脉制备物中使用FITC标记的白蛋白进行的活体显微镜研究表明，CysLT介导的快速渗透性可通过应用BAY-u9773（一种CysLT（1）R/CysLT（2）R双重拮抗剂）或CysLT（2）R缺乏而阻断。即使在没有外源性配体的情况下，小鼠中的内皮人CysLT 2 R过表达也会加剧血管渗漏。由CysLT 2 R介导的增强的血管通透性通过跨内皮囊泡转运机制而不是细胞旁途径发生，并且通过Ca 2+信号传导控制。我们的研究结果表明，CysLT 2 R可以介导的炎症反应，在血管床特异性的方式，通过改变跨内皮小泡运输为基础的血管通透性。Moos，M. P.W.，Mewburn，J.D.，Kan，F. W. K.，石井，S.，Abe，M.，Sakimura，K.，Noguchi，K.，清水，T.，芬克角D.半胱氨酰白三烯2受体通过跨内皮囊泡转运介导的血管通透性。FASEB J. 22，4352-4362（2009）
Cysteinyl leukotrienes (CysLTs) are potent mediators of inflammation synthesized by the concerted actions of 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), leukotriene C4 synthase, and additional downstream enzymes, starting with arachidonic acid substrate. CysLTs produced by macrophages, eosinophils, mast cells, and other inflammatory cells activate 3 different high-affinity CysLT receptors: CysLT1R, CysLT2R, and GPR 17. We sought to investigate vascular sites of CysLT2R expression and the role and mechanism of this receptor in mediating vascular permeability events. Vascular expression of CysLT2R was investigated by reporter gene expression in a novel CysLT2R deficient-LacZ mouse model. CysLT2R was expressed in small, but not large, vessels in mouse brain, bladder, skin, and cremaster muscle. Intravital, in addition to confocal and electron, microscopy investigations using FITC-labeled albumin in cremaster postcapillary venule preparations indicated rapid CysLT-mediated permeability, which was blocked by application of BAY-u9773, a dual CysLT(1)R/CysLT(2)R antagonist or by CysLT2R deficiency. Endothelial human CysLT2R overexpression in mice exacerbated vascular leakage even in the absence of exogenous ligand. The enhanced vascular permeability mediated by CysLT2R takes place via a transendothelial vesicle transport mechanism as opposed to a paracellular route and is controlled via Ca2+ signaling. Our results reveal that CysLT2R can mediate inflammatory reactions in a vascular bed-specific manner by altering transendothelial vesicle transport-based vascular permeability. Moos, M. P. W., Mewburn, J. D., Kan, F. W. K., Ishii, S., Abe, M., Sakimura, K., Noguchi, K., Shimizu, T., Funk, C. D. Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport. FASEB J. 22, 4352-4362 (2009)