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.

血浆尿紧张素II（UII）水平升高与动脉粥样硬化呈正相关。在这项研究中，我们调查了巨噬细胞分泌的UII在动脉粥样硬化进展中的作用，并评估了动脉粥样硬化治疗中有效的竞争性UII受体拮抗剂urantide的治疗价值。巨噬细胞特异性人类UII转基因兔和其非转基因同窝仔接受高胆固醇饮食喂养16周，以诱发动脉粥样硬化。主动脉粥样硬化病变的细胞成分（巨噬细胞和平滑肌细胞）的免疫组织化学染色显示，与非转基因同窝仔猪相比，仅雄性转基因兔的巨噬细胞阳性区域显着增加（52％）。然而，与对照组相比，雄性和雌性转基因兔子的平滑肌细胞阳性面积均显着降低（雄性为45％，雌性为31％）。巨噬细胞分泌的UII对斑块细胞成分的影响与血浆脂质水平无关。同时，对野生型兔子连续皮下注入尿嘧啶（5.4 µg·kg）。^-1 ·h ^-1）使用渗透微型泵。输注尿嘧啶的作用与UII引起的相反，因为与对照兔相比，它显着降低了雄性野生型兔子的巨噬细胞阳性面积。在培养的人脐静脉内皮细胞中，UII剂量依赖性地增加了粘附分子VCAM-1和ICAM-1的表达，这种作用被尿嘧啶部分逆转。目前的研究提供了直接的证据，表明巨噬细胞分泌的UII在动脉粥样硬化中起关键作用。用尿嘧啶靶向UII可通过减少巨噬细胞衍生的泡沫细胞形成来促进斑块稳定性，这是不稳定斑块的指标。