Therapeutic ultrasound combined with microbubbles improves atherosclerotic plaque stability by selectively destroying the intraplaque neovasculature
Therapeutic ultrasound combined with microbubbles improves atherosclerotic plaque stability by selectively destroying the intraplaque neovasculature
复制标题
治疗性超声与微泡相结合，通过选择性破坏斑块内的新生血管来改善动脉粥样硬化斑块的稳定性
DOI：
10.7150/thno.39553
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Bin, Jianping
中科院分区：
文献类型：
--
作者：
Li, Xinzhong;Guo, Shengcun;Bin, Jianping
目的：目前动脉粥样硬化斑块的抗血管生成治疗主要通过使用抗血管生成药物来实现，但严重的副作用限制了临床应用。本研究探讨适当压力下的治疗性超声（TUS）治疗是否可以选择性地消耗易损斑块中的新生血管以提高其稳定性，同时对身体无副作用；还探讨了潜在的机制。方法和结果：通过高胆固醇血症饮食（HCD）维持载脂蛋白e缺乏（ApoE-/-）小鼠，产生晚期动脉粥样硬化小鼠模型。对114只动脉粥样硬化小鼠的斑块、骨骼肌、肠系膜和皮肤组织进行假治疗，在四种不同的超声压力（1.0、2.0、3.0、5.0 MPa）下进行超声联合微泡治疗，或单独在5.0 MPa下进行超声治疗。采用免疫荧光和免疫组织化学方法测定微血管密度（MVD）。计算斑块坏死中心/纤维帽（NC/FC）比值及易损性指数评价斑块易损性。3.0 MPa TUS治疗24小时后，斑块内MVD显著降低84% (p < 0.05)，而骨骼肌、肠系膜、皮肤等正常组织的MVD和新生血管密度（NVD）几乎没有变化。此外，斑块中未成熟血管的数量显著减少（减少了90%，p < 0.05），而成熟血管的数量没有显著减少。此外，3.0 MPa的TUS治疗显著提高了斑块的稳定性，体现在NC/FC比值和易损指数上，这可能是由于TUS治疗选择性地破坏斑块内新生血管，从而减少红细胞外溢，导致血管炎症减轻，薄帽纤维粥样硬化减少。结论：3.0 MPa的TUS治疗通过减少红细胞外渗和炎症介质内流，选择性地耗尽斑块新生血管，提高易损斑块的稳定性，对正常组织无明显影响。
Objective: The current antiangiogenic therapy for atherosclerotic plaques was mainly achieved by the use of antiangiogenic drugs, but serious side effects have limited the clinical application. The present study investigated whether therapeutic ultrasound (TUS) treatment with appropriate pressure could selectively deplete the neovasculature in vulnerable plaques to improve its stability with no side effects on the body; the underlying mechanisms were also explored. Methods and Results: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE-/-) mice on a hypercholesterolemic diet (HCD). Plaque, skeletal muscle, mesentery and skin tissue from 114 atheroma-bearing mice were subjected to sham therapy, an ultrasound application combined with microbubbles at four different ultrasound pressures (1.0, 2.0, 3.0, 5.0 MPa), or ultrasound at 5.0 MPa alone. Microvessel density (MVD) was assessed by immunofluorescence and immunohistochemical methods. The plaque necrotic center/fiber cap (NC/FC) ratio and vulnerability index were calculated to evaluate plaque vulnerability. Twenty-four hours after TUS treatment at 3.0 MPa, the MVD in the plaque was substantially decreased by 84% (p < 0.05), while there was almost no change in MVD and neovessel density (NVD) in normal tissues, including skeletal muscle, mesentery and skin. Additionally, a marked reduction in the number of immature vessels was observed in the plaques (reduced by 90%, p < 0.05), whereas the number of mature vessels was not significantly decreased. Furthermore, TUS treatment at 3.0 MPa significantly improved plaque stability, as reflected by the NC/FC ratio and vulnerability index, which may be due to the selective destruction of intraplaque neovascularization by TUS treatment, thereby decreasing the extravasation of erythrocytes and leading to vascular inflammation alleviation and thin-cap fibroatheroma reduction. Conclusions: TUS treatment at 3.0 MPa selectively depleted plaque neovessels and improved the stability of vulnerable plaques through a reduction in erythrocyte extravasation and inflammatory mediator influx, with no significant effect on normal tissue.