Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China.
Theranostics. 2020 Jan 22;10(6):2522-2537. doi: 10.7150/thno.39553. eCollection 2020.
: 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. : 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. : 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.
: 目前，抗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其临床应用。本研究旨在探讨适当压力的治疗性超声（TUS）治疗是否可以选择性地耗尽易损斑块中的新生血管，从而提高其稳定性，同时对身体没有副作用；还探讨了其潜在机制。 : 通过让载脂蛋白 E 缺陷（ApoE-/-）小鼠在高胆固醇饮食（HCD）上维持，生成了晚期动脉粥样硬化的小鼠模型。对 114 只动脉粥样硬化斑块小鼠的斑块、骨骼肌、肠系膜和皮肤组织进行假治疗、超声联合微泡在四种不同超声压力（1.0、2.0、3.0、5.0 MPa）下应用或单独 5.0 MPa 超声处理。通过免疫荧光和免疫组织化学方法评估微血管密度（MVD）。计算斑块坏死中心/纤维帽（NC/FC）比和易损性指数以评估斑块易损性。在 3.0 MPa 的 TUS 治疗后 24 小时，斑块中的 MVD 显著降低了 84%（p < 0.05），而正常组织（包括骨骼肌、肠系膜和皮肤）中的 MVD 和新生血管密度（NVD）几乎没有变化。此外，在斑块中观察到不成熟血管的数量明显减少（减少了 90%，p < 0.05），而成熟血管的数量没有明显减少。此外，3.0 MPa 的 TUS 治疗显著改善了斑块稳定性，这反映在 NC/FC 比和易损性指数上，这可能是由于 TUS 治疗选择性地破坏了斑块内的新生血管，从而减少了红细胞外渗，导致血管炎症缓解和薄帽纤维粥样瘤减少。 : 3.0 MPa 的 TUS 治疗通过减少红细胞外渗和炎症介质的涌入选择性地耗尽斑块新生血管，并改善易损斑块的稳定性，对正常组织没有显著影响。
