Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport

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)