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 C(4) 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: CysLT(1)R, CysLT(2)R, and GPR 17. We sought to investigate vascular sites of CysLT(2)R expression and the role and mechanism of this receptor in mediating vascular permeability events. Vascular expression of CysLT(2)R was investigated by reporter gene expression in a novel CysLT(2)R deficient-LacZ mouse model. CysLT(2)R 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 CysLT(2)R deficiency. Endothelial human CysLT(2)R overexpression in mice exacerbated vascular leakage even in the absence of exogenous ligand. The enhanced vascular permeability mediated by CysLT(2)R takes place via a transendothelial vesicle transport mechanism as opposed to a paracellular route and is controlled via Ca(2+) signaling. Our results reveal that CysLT(2)R can mediate inflammatory reactions in a vascular bed-specific manner by altering transendothelial vesicle transport-based vascular permeability.
Moos
Michael P W
MP
Department of Physiology, Queen's University, Kingston, ON K7L 3N6, Canada.
Mewburn
Jeffrey D
JD
Kan
Frederick W K
FW
Ishii
Satoshi
S
Abe
Manabu
M
Sakimura
Kenji
K
Noguchi
Kyoko
K
Shimizu
Takao
T
Funk
Colin D
CD
D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D002199:Capillary Permeability / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D015870:Gene Expression; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000502:physiology*; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D012709:Serum Albumin
C071435:BAY u9773; C518288:FITC-albumin; D018077:Receptors, Leukotriene; D013189:SRS-A; D012709:Serum Albumin; C412375:cysteinyl leukotriene receptor 2; D016650:Fluorescein-5-isothiocyanate