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Increasing levels of plasma urotensin Ⅱ (UⅡ) are positively associated with atherosclerosis.In this study we investigated the role of macrophage-secreted UⅡ in atherosclerosis progression,and evaluated the therapeutic value of urantide,a potent competitive UⅡ receptor antagonist,in atherosclerosis treatment.Macrophage-specific human UⅡ-transgenic rabbits and their nontransgenic littermates were fed a high cholesterol diet for 16 weeks to induce atherosclerosis.Immunohistochemical staining of the cellular components (macrophages and smooth muscle cells) of aortic atherosclerotic lesions revealed a significant increase (52％) in the macrophage-positive area in only male transgenic rabbits compared with that in the nontransgenic littermates.However,both male and female transgenic rabbits showed a significant decrease (45％ in males and 31％ in females) in the smooth muscle cell-positive area compared with that of their control littermates.The effects of macrophage-secreted UⅡ on the plaque cellular components were independent of plasma lipid level.Meanwhile the wild-type rabbits were continuously subcutaneously infused with urantide (5.4 μg· kg-1· h-1) using osmotic mini-pumps.Infusion of urantide exerted effects opposite to those caused by UⅡ,as it significantly decreased the macrophage-positive area in male wild-type rabbits compared with that of control rabbits.In cultured human umbilical vein endothelial cells,treatment with UⅡ dose-dependently increased the expression of the adhesion molecules VCAM-1 and ICAM-1,and this effect was partially reversed by urantide.The current study provides direct evidence that macrophage-secreted UⅡ plays a key role in atherogenesis.Targeting UⅡ with urantide may promote plaque stability by decreasing macrophage-derived foam cell formation,which is an indicator of unstable plaque.