Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia.

Cysteinyl leukotrienes (i.e. LTC(4), LTD(4)), produced by activated leukocytes or by transcellular metabolism may act at different levels on vascular smooth muscle cells (VSMC) during inflammatory processes or atherosclerosis. We studied the effect of LTC(4), LTD(4), and LTE(4) on the in vitro proliferation of rat VSMC, measured by [H-3]-thymidine incorporation and cell count. LTD(4) had a stronger stimulatory effect on [H-3]-thymidine incorporation than LTC(4), whereas LTE(4) was inactive. The effect of LTD(4) on [H-3]-thymidine incorporation was dose-dependent, with the maximal activity at 10(-6) M. The stimulatory activity of LTD(4) was inhibited in a dose-dependent manner by MK-571, a specific LTD(4) receptor antagonist. In addition, MK-571 (1 mg/kg/day) given for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, provided effective inhibition of myointimal VSMC proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening. Our data support the importance of inflammatory mechanisms in the pathogenesis of atherosclerosis and suggest a possible role for cysteinyl leukotrienes, specifically LTD(4), in the control of VSMC proliferation.