WEB2086对载脂蛋白E基因缺陷小鼠动脉粥样硬化斑块和缺血后肢血管生成的相反作用。
Opposite effects of WEB2086 on angiogenesis in atheromas and ischemic hindlimb of apoE gene deficient mice.
作者信息
Wang Shuang, Tang Ya-ling, Yang Yong-zong, Xu Zeng-xiang, Peng Kuang
机构信息
Department of Pathophysiology, Xiangya Medical College, Central South University, Changsha 410078, China.
出版信息
Chin Med J (Engl). 2007 May 20;120(10):886-92.
BACKGROUND
Our previous research has suggested that platelet activating factor receptor was related to atherosclerosis. The present study investigated the effect of a platelet activating factor receptor antagonist-WEB2086 on angiogenesis in aortal plaque and ischemic hindlimb of apolipoprotein E-deficient mice.
METHODS
Eight-week-old apolipoprotein E-deficient mice were fed with a 0.15% cholesterol diet to develop advanced lesions. At age 32 weeks unilateral hindlimb ischemia was surgically induced and the mice were divided into two groups: with or without WEB2086 mixed with their drinking water (4.3 mg in 100 ml). At age 40 weeks blood was collected from the orbit for measurement of serum lipids and an enzyme linked immunosorbent assay was used to determine platelet activating factor and oxidized low density lipoprotein in the gastrocnemius and aorta. Whole-Mount CD31 stain and plaque-associated sprouting have been used to estimate angiogenesis in plaque from the aorta and laser Doppler perfusion imaging and immunohistochemical expression of von Willebrand factor have been used to estimate angiogenesis in ischemic hindlimb.
RESULTS
The lipid composition of serum was not different between the groups. However, the amount of platelet activating factor and oxidized low density lipoprotein detected in the aorta was significantly higher than that in the gastrocnemius of ischemic hindlimb. The ratio of lesion to aorta levels was significantly reduced by administration of WEB2086, (31.52 +/- 6.18)% vs (55.58 +/- 8.34)%, P < 0.01. The mean density of intimal capillaries in atherosclerotic plaque, (31.13 +/- 9.20)% vs (57.74 +/- 11.28)%, P < 0.01, and the mean number of sprouts per aorta were significantly reduced, 183.92 +/- 34.17 vs 392.54 +/- 76.79, P < 0.01, in the WEB2086 group. Blood flow (0.85 +/- 0.12 vs 0.45 +/- 0.06, P < 0.01) and capillary density of ischemic hindlimb (1.18 +/- 0.17 vs 0.53 +/- 0.09, P < 0.01) were markedly increased in apolipoprotein E-deficient mice treated with WEB2086 versus controls.
CONCLUSION
The study provides evidence that WEB2086 can inhibit angiogenesis in atherosclerotic plaque but promote it in ischemic hindlimb.
背景
我们之前的研究表明血小板活化因子受体与动脉粥样硬化有关。本研究调查了血小板活化因子受体拮抗剂-WEB2086对载脂蛋白E缺乏小鼠主动脉斑块和缺血后肢血管生成的影响。
方法
8周龄的载脂蛋白E缺乏小鼠喂食0.15%胆固醇饮食以形成晚期病变。32周龄时通过手术诱导单侧后肢缺血，将小鼠分为两组：一组饮用水中混合有WEB2086（100 ml中含4.3 mg），另一组没有。40周龄时从眼眶采集血液测量血脂，采用酶联免疫吸附测定法测定腓肠肌和主动脉中的血小板活化因子和氧化低密度脂蛋白。采用全层CD31染色和斑块相关发芽来评估主动脉斑块中的血管生成，采用激光多普勒灌注成像和血管性血友病因子的免疫组化表达来评估缺血后肢的血管生成。
结果
两组血清脂质成分无差异。然而，主动脉中检测到的血小板活化因子和氧化低密度脂蛋白的量明显高于缺血后肢的腓肠肌。给予WEB2086后，病变与主动脉水平的比值显著降低，分别为(31.52±6.18)%和(55.58±8.34)%，P<0.01。WEB2086组动脉粥样硬化斑块内膜毛细血管的平均密度显著降低，分别为(31.13±9.20)%和(57.74±11.28)%，P<0.01，每主动脉的平均发芽数也显著减少，分别为183.92±34.17和392.54±76.79，P<0.01。与对照组相比，用WEB2086治疗的载脂蛋白E缺乏小鼠缺血后肢的血流量（0.85±0.12对0.45±0.06，P<0.01）和毛细血管密度（1.18±0.17对0.53±0.09，P<0.01）明显增加。
结论
该研究提供了证据表明WEB2086可抑制动脉粥样硬化斑块中的血管生成，但促进缺血后肢的血管生成。
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