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Cardiovascular Research 2007 76(1):160-166; doi:10.1016/j.cardiores.2007.05.018
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Copyright © 2007, European Society of Cardiology

Role of cysteinyl leukotrienes in the proliferation and the migration of murine vascular smooth muscle cells in vivo and in vitro

Yasuhiro Kaetsua, Yasutaka Yamamotob,*, Shinobu Sugiharab, Takashi Matsuuraa, Go Igawaa, Koichi Matsubaraa, Osamu Igawaa, Chiaki Shigemasaa and Ichiro Hisatomeb

aDepartment of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, Yonago, Japan
bDivision of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan

*Corresponding author. Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, 36-1 Nishi-machi, Yonago 683-8504, Japan. Tel.: +81 859 38 6517; fax: +81 859 38 6519. yasutaka{at}grape.med.tottori-u.ac.jp

Objective Cysteinyl leukotrienes (Cys-LTs) are proinflammatory lipid mediators generated from arachidonic acid through 5-lipoxygenase (5-LO). It was reported that the 5-LO pathway is associated with vascular smooth muscle cell (VSMC) proliferation and migration; however, the relationship between Cys-LTs and VSMC proliferation and migration remains unclear.

Methods: We used a mouse (C57/BL6J) model of femoral artery wire injury, and compared neointimal formation between controls and animals treated with the Cys-LT receptor antagonist, Montelukast (3 mg/kg/day). The effects of Cys-LTs with or without Montelukast on mouse aortic VSMC proliferation and migration were also investigated.

Results After wire injury, neointimal hyperplasia was observed, and immunohistochemical analysis demonstrated expression of the Cys-LT receptors (Cys-LT1 and Cys-LT2) and {alpha}-smooth muscle actin in the injured arterial walls. RT-PCR analysis revealed that transcription was not altered during the observation period (before, 1, 2 and 4 weeks after injury). Administration of Montelukast significantly inhibited neointimal formation 4 weeks after injury (intima/media ratio; control group 1.94±0.56 versus Montelukast-treated group 0.94±0.26, n=11, P<0.001). In an in vitro study, LTD4, but not LTC4 and LTE4 significantly stimulated VSMC proliferation (1000 nM), and this effect was inhibited by Montelukast (10 µM). LTC4, LTD4 and LTE4 significantly stimulated VSMC migration (1000 nM), and this effect was inhibited by Montelukast (10 µM).

Conclusions Our data suggest that Cys-LTs are involved in VSMC proliferation and migration, and a Cys-LT receptor antagonist may have beneficial effects on vascular remodeling after mechanical injury.

KEYWORDS Inflammation; Remodeling; Smooth muscle cells


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