Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure.
BACKGROUND
The proinflammatory and vascular actions of cysteinyl leukotrienes (CysLTs) are mediated by 2 receptors: cysteinyl leukotriene 1 receptor (CysLT1R) and cysteinyl leukotriene 2 receptor (CysLT2R). However, the distinct contribution of CysLT2R to the vascular actions of CysLTs has not been addressed.


RESULTS
We generated an endothelial cell-specific human CysLT2R (EC-hCysLT2R) transgenic (TG) mouse model using the Tie2 promoter/enhancer. Strong expression of hCysLT2R in TG lung and endothelial cells, detected by real-time polymerase chain reaction, markedly enhanced CysLT-stimulated intracellular calcium mobilization compared with endogenous expression in cells from nontransgenic mice. The permeability response to exogenous LTC4 and to endogenous CysLTs evoked by passive cutaneous anaphylaxis was augmented in TG mice. The rapid, systemic pressor response to intravenous LTC4 was also diminished in TG mice coincidentally with augmented production of nitric oxide.


CONCLUSIONS
The development of EC-hCysLT2R mice has permitted detection of distinct vascular effects of CysLTs, which can be mediated via the CysLT2R in vivo.
Hui
Yiqun
Y
Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pa, USA.
Cheng
Yan
Y
Smalera
Isabella
I
Jian
Wenying
W
Goldhahn
Lawrence
L
Fitzgerald
Garret A
GA
Funk
Colin D
CD
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability; D004431:Ear, External / Q000098:blood supply; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology*; D017997:Leukotriene C4 / Q000494:pharmacology*; D008168:Lung / Q000166:cytology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000097:blood / Q000502:physiology; D010323:Passive Cutaneous Anaphylaxis / Q000502:physiology; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017997:Leukotriene C4; D009569:Nitric Oxide; C412375:cysteinyl leukotriene receptor 2