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(Circulation. 2004;110:3360-3366.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Directed Vascular Expression of Human Cysteinyl Leukotriene 2 Receptor Modulates Endothelial Permeability and Systemic Blood Pressure

Yiqun Hui, MD, PhD; Yan Cheng, MD, PhD; Isabella Smalera, MS; Wenying Jian, MS; Lawrence Goldhahn, BS; Garret A. FitzGerald, MD; Colin D. Funk, PhD

From the Center for Experimental Therapeutics and Department of Pharmacology (Y.H., Y.C., W.J., L.G., G.A.F., C.D.F.), University of Pennsylvania, Philadelphia, Pa; Merck Research Laboratories, Department of Cardiovascular Diseases, Rahway, NJ (I.S.); and the Departments of Physiology and Biochemistry, Queen’s University, Kingston, Ontario, Canada (C.D.F.).

Correspondence to Colin D. Funk, PhD, Department of Physiology, Queen’s University, Kingston, ON K7L 3N6 Canada. E-mail funkc{at}post.queensu.ca

Received May 14, 2004; revision received August 9, 2004; accepted August 23, 2004.

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.

Methods and 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.

Key Words: leukotrienes • receptors • endothelium • edema • blood pressure

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