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

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 formation4 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 mu M). LTC4, LTD4 and LTE4 significantly stimulated VSMC migration (1000 nM), and this effect was inhibited by Montelukast (10 mu M). 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. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.