Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice
Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice
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DOI：
10.1161/01.cir.99.13.1726
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发表时间：
1999-04-06
期刊：
影响因子：
37.8
通讯作者：
Folkman, J
中科院分区：
文献类型：
--
作者：
Moulton, KS;Heller, E;Folkman, J
背景-人类动脉粥样硬化病变内膜内的新血管形成已被充分描述，但其在动脉粥样硬化进展中的作用尚不清楚。在这份报告中，我们首先证明内膜血管发生在载脂蛋白E缺陷（apoE -/-）小鼠的晚期病变。为了验证内膜血管促进动脉粥样硬化的假设，我们研究了血管生成抑制剂对apoE -/-mouse.Methods和Results-ApoE -/-mouse中斑块生长的影响。在20周龄时，将小鼠分成3组并如下处理16周：第1组，重组小鼠内皮抑制素，20mg.kg;第2组，烟曲霉素类似物TNP-470，30 mg/kg，每隔一天;和第3组，接受类似体积缓冲液的对照动物。所有组的平均胆固醇水平相似。在主动脉起始处定量斑块面积。治疗前斑块面积中位数为0.250 mm（2）（范围：0.170 - 0.348; n=10）。内皮抑制素组、TNP-470组和对照组的中位斑块面积分别为0.321（0.238 - 0.412; n= 10）、0.402（0.248 - 0.533; n=15）和0.751 mm（2）（0.503 - 0.838; n=12）（P ≤ 0.0001）。因此，内皮抑素和TNP-470在治疗期间抑制了85%和70%的斑块生长。对照组和治疗组小鼠斑块的内膜平滑肌细胞含量相似。结论：血管生成抑制剂延长治疗可减少apoE -/-小鼠斑块生长和内膜新生血管形成。虽然这些药物诱导的斑块抑制机制尚未建立，但这些结果表明内膜新生血管可能促进斑块发展。
Background-Neovascularization within the intima of human atherosclerotic lesions is well described, but its role in the progression of atherosclerosis is unknown. In this report, we first demonstrate that intimal vessels occur in advanced lesions of apolipoprotein E-deficient (apoE -/-) mice. To test the hypothesis that intimal vessels promote atherosclerosis, we investigated the effect of angiogenesis inhibitors on plaque growth in apoE -/- mice.Methods and Results-ApoE -/- mice were fed a 0.15% cholesterol diet. At age 20 weeks, mice were divided into 3 groups and treated for 16 weeks as follows: group 1, recombinant mouse endostatin, 20 mg.kg(-1).d(-1); group 2, fumagillin analogue TNP-470, 30 mg/kg every other day; and group 3, control animals that received a similar volume of buffer. Average cholesterol levels were similar in all groups. Plaque areas were quantified at the aortic origin. Median plaque area before treatment was 0.250 mm(2) (range, 0.170 to 0.348; n=10). Median plaque areas were 0.321 (0.238 to 0.412; n=10), 0.402 (0.248 to 0.533; n=15), and 0.751 mm(2) (0.503 to 0.838; n=12) for the endostatin, TNP-470, and control groups, respectively (P less than or equal to 0.0001). Therefore, endostatin and TNP-470 inhibited plaque growth during the treatment period by 85% and 70%. Intimal smooth muscle cell contents of plaques from control and treated mice were similar,Conclusions-Prolonged treatment with either angiogenesis inhibitor reduced plaque growth and intimal neovascularization in apoE -/- mice. Although the mechanism of plaque inhibition induced by these agents is not established, these results suggest that intimal neovascularization may promote plaque development.