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

Abstract

Background-The proinflammatory and vascular actions of cysteinyl leukotrienes (CysLTs) are mediated by 2 receptors: cysteinyl leukotriene 1 receptor (CysLT 1 R) and cysteinyl leukotriene 2 receptor (CysLT 2 R). However, the distinct contribution of CysLT 2 R to the vascular actions of CysLTs has not been addressed. Methods and Results-We generated an endothelial cell-specific human CysLT 2 R (EC-hCysLT 2 R) transgenic (TG) mouse model using the Tie2 promoter/enhancer. Strong expression of hCysLT 2 R 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 LTC 4 and to endogenous CysLTs evoked by passive cutaneous anaphylaxis was augmented in TG mice. The rapid, systemic pressor response to intravenous LTC 4 was also diminished in TG mice coincidentally with augmented production of nitric oxide. Conclusions-The development of EC-hCysLT 2 R mice has permitted detection of distinct vascular effects of CysLTs, which can be mediated via the CysLT 2 R in vivo.

Leukotriene Signaling in Atherosclerosis and Ischemia

“…The latter notion has in addition received support from animal models. Directed endothelial expression of the human CysLT 2 receptor in mice induces an enhanced NO production in response to LTC 4 , but does not change baseline systemic blood pressure compared with wild type mice [46]. Furthermore, although the LT synthesis inhibitor MK-886 (Fig.…”

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

“…The right internal jugular vein and left carotid artery were cannulated with PE-10 tubing. The arterial catheter was connected to a Capto SP844 pressure transducer (GE Healthcare - Capto), and blood pressure was monitored continuously with a PowerLab/8SP system (ADInstruments), as previously described (56,57). Blood pressure and heart rate were continuously monitored for 20-40 minutes until stable values were obtained.…”

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

“…LT-Rs are expressed on multiple target cells, including leukocytes, smooth muscle cells, and ECs (1). Recent studies implicate the 5-LO pathway in cardiovascular disease (11)(12)(13)(14)(15)(16)(17).Considerable information is available on cysLT 1 -R, whereas little is known about cysLT 2 -R. We have used human umibilical vein (HUV)ECs as a model of vascular cells to study cysLT 2 -R activation by demonstrating that cysLTs exclusively signal through cysLT 2 -R in this cell type (18): In fact, HUVECs are the first primary cell type that selectively expresses cysLT 2 -R. In the study detailed below, we determined HUVEC gene signatures in response to LTD 4 and characterized the resulting phenotypes. LTD 4 responses were compared with those of the prototype vasoactive agonist thrombin, which, in HUVEC, acts through protease-activated receptor (PAR)-1 (19).…”

“…LT-Rs are expressed on multiple target cells, including leukocytes, smooth muscle cells, and ECs (1). Recent studies implicate the 5-LO pathway in cardiovascular disease (11)(12)(13)(14)(15)(16)(17).…”