Published Online
on November 15, 2004

A more recent version of this article appeared on November 23, 2004

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Submitted on May 14, 2004
Revised on August 9, 2004
Accepted on August 23, 2004

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, and 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.).

^* To whom correspondence should be addressed. E-mail: funkc{at}post.queensu.ca.

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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Circulation 2004 110: 3289. [Extract] [Full Text]

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