Moulton K S, Heller E, Konerding M A, Flynn E, Palinski W, Folkman J
Surgical Research Laboratory, Children's Hospital, Boston MA, USA.
Circulation. 1999 Apr 6;99(13):1726-32. doi: 10.1161/01.cir.99.13.1726.
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.
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 mm2 (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 mm2 (0.503 to 0.838; n=12) for the endostatin, TNP-470, and control groups, respectively (P</=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.
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.
人类动脉粥样硬化病变内膜中的新生血管形成已有充分描述，但其在动脉粥样硬化进展中的作用尚不清楚。在本报告中，我们首先证明内膜血管出现在载脂蛋白E缺陷（apoE -/-）小鼠的晚期病变中。为了验证内膜血管促进动脉粥样硬化的假说，我们研究了血管生成抑制剂对apoE -/-小鼠斑块生长的影响。
给apoE -/-小鼠喂食0.15%胆固醇饮食。在20周龄时，将小鼠分为3组并进行如下处理16周：第1组，重组小鼠内皮抑素，20 mg·kg-1·d-1；第2组，烟曲霉素类似物TNP-470，每隔一天30 mg/kg；第3组，接受相似体积缓冲液的对照动物。所有组的平均胆固醇水平相似。在主动脉起始处对斑块面积进行定量。治疗前的中位斑块面积为0.250 mm2（范围，0.170至0.348；n = 10）。内皮抑素组、TNP-470组和对照组的中位斑块面积分别为0.321（0.238至0.412；n = 10）、0.402（0.248至0.533；n = 15）和0.751 mm2（0.503至0.838；n = 12）（P≤0.0001）。因此，内皮抑素和TNP-470在治疗期间分别将斑块生长抑制了85%和70%。对照小鼠和治疗小鼠斑块中的内膜平滑肌细胞含量相似。
用任何一种血管生成抑制剂进行长期治疗均可减少apoE -/-小鼠的斑块生长和内膜新生血管形成。尽管这些药物诱导斑块抑制的机制尚未明确，但这些结果表明内膜新生血管形成可能促进斑块发展。
