The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque.
The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque.
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DOI：
10.1161/circresaha.108.184622
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发表时间：
2009-02-13
影响因子：
20.1
通讯作者：
Mulligan-Kehoe MJ
中科院分区：
文献类型：
--
作者：
Drinane M;Mollmark J;Zagorchev L;Moodie K;Sun B;Hall A;Shipman S;Morganelli P;Simons M;Mulligan-Kehoe MJ
斑块血管分布与其生长和稳定性有关。然而，关于斑块脉管系统的起源和滋养血管在斑块生长中的作用的信息很少。在本研究中，我们使用具有显着抗血管生成活性的截短 PAI-1 蛋白 rPAI-123 来抑制致动脉粥样硬化小鼠的血管滋养管生长，并评估其对斑块生长的影响。雌性 LDLR−/− ApoB-48 缺陷小鼠喂食不含胆酸的 Paigen 饮食 20 周，并在最后六周接受 rPAI-1 23 治疗 (n = 21)。将斑块大小和滋养血管密度与两个对照进行比较，即在最后六周喂食 Paigen 饮食并用盐水治疗的小鼠 (n = 16)，以及在治疗开始之前喂食 Paigen 饮食的小鼠 (n = 14)。 rPAI-123治疗显着减少了降主动脉中的斑块面积和斑块胆固醇以及无名动脉中的斑块面积。血管滋养管重建共聚焦显微镜图像的测量表明，rPAI-123 治疗减少了血管滋养管的面积和长度，这一点得到了 microCT 图像的支持。共聚焦图像提供了盐水治疗组中血管斑块的证据，但 rPAI-123 治疗组中则没有。经盐水处理的小鼠血管密度增加部分是由于 FGF-2 表达上调，而 FGF-2 表达被 rPAI-123 抑制。总之，rPAI-123 通过抑制 FGF-2 抑制血管滋养管以及邻近斑块和血管壁内的血管生长，从而减少致动脉粥样硬化雌性 LDLR−/− ApoB-48 缺陷小鼠的斑块生长。
Plaque vascularity has been implicated in its growth and stability. However, there is a paucity of information regarding the origin of plaque vasculature and the role of vasa vasorum in plaque growth. In this study we used a truncated PAI-1 protein, rPAI-123, that has significant anti-angiogenic activity, to inhibit growth of vasa vasorum in atherogenic mice and assessed its effect on plaque growth. Female LDLR−/− ApoB-48 deficient mice fed Paigen’s diet without cholate for 20 weeks received rPAI-1 23 treatment (n= 21) for the last six weeks. Plaque size and vasa vasorum density were compared to two controls, mice fed Paigen’s diet and treated with saline for the last six weeks (n=16) and mice fed Paigen’s diet until the onset of treatment (n=14). The rPAI-123 treatment significantly reduced plaque area and plaque cholesterol in the descending aorta and plaque area in the innominate artery. Measurements of reconstructed confocal microscopy images of vasa vasorum demonstrate that rPAI-123 treatment decreased vasa vasorum area and length, which was supported by microCT images. Confocal images provide evidence for vascularized plaque in the saline treated group, but not in rPAI-123 treated mice. The increased vessel density in saline treated mice is due, in part, to upregulated FGF-2 expression, which is inhibited by rPAI-123. In conclusion, rPAI-123 inhibits growth of vasa vasorum as well as vessels within the adjacent plaque and vessel wall through inhibition of FGF-2, leading to reduced plaque growth in atherogenic female LDLR−/− ApoB-48 deficient mice.