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

Michael P. W. Moos^*, Jeffrey D. Mewburn, Frederick W. K. Kan, Satoshi Ishii^||,¶, Manabu Abe^#, Kenji Sakimura^#, Kyoko Noguchi^||, Takao Shimizu^|| and Colin D. Funk^*,,1

^* Department of Physiology,

Department of Biochemistry,

Division of Cancer Biology and Genetics, Cancer Research Institute, and

Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada;

^|| Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan;

^¶ Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan; and

^# Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata City, Japan

¹Correspondence: Department of Physiology, 433 Botterell Hall, Stuart St., Queen’s University, Kingston, ON K7L 3N6, Canada. E-mail: funkc{at}queensu.ca

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 CysLT₁R/CysLT₂R 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.

Key Words: inflammation • intravital microscopy • transgenic mice • caveolae