超声联合微泡干预治疗选择性毁损新生滋养血管稳定易损斑块的实验研究

Increasing number of investigations have focused on the treatment for regression and stabilization of vulnerable plaques. Accumulated evidence has shown that neo-vasavasom in plaques are closely associated with plaque vulnerability, indicating that these neovessels can serve as a novel target for the treatment of vulnerable plaques. However, systemic antiangiogenic agents without plaque-targeting have shown limited success in clinical practice because of systemic adverse effects. Ultrasound-microbubble treatment (UMT) is a promising alternative method of targeting the neo-vasavasom in plaques, since ultrasound-driven cavitation causes direct and localized mechanical damage on vessel walls. Our previous studies have demonstrated that low-intensity UMT selectively depletes neovasculature in the tumor. We, therefore, hypothesized that low-intensity UMT is capable to selectively deplete neovasculature in the plaques and consequently improve the plaque vulnerability. This project is proposed to: (1) verify the correlation between neovasculature in the plaques and plaque vulnerability; (2) explore the appropriate ultrasound energy for selectively depleting neovasculature in the plaques, and its physical effects; (3) evaluate the effect of UMT on regression and stabilization of vulnerable plaques and its pathological mechanism by histological examinations, immunohistochemistry, immunofluorescence staining, transimission electron microscopy, and dextran penetration test, so as to develop an efficient and safe approach for the treatment of vulnerable plaques.

稳定和逆转易损斑块干预治疗研究是目前的热点。研究显示：斑块内新生滋养血管与易损性密切相关，表明斑块内血管新生是治疗易损斑块的新靶点，然而抑制血管新生药物的治疗缺乏靶向性，其全身毒副作用严重限制了其临床应用。超声联合微泡所致的空化效应可以对血管壁产生直接和局部的物理损伤效应，无全身毒副作用，而且我们前期的研究已证实低能超声联合微泡能选择性毁损肿瘤新生血管。因此，我们提出假设：低能超声联合微泡治疗技术能选择性毁损斑块内新生的滋养血管从而改善斑块的易损性。本项目拟采用组织病理、免疫组化、免疫荧光、透射电镜和葡聚糖渗透实验等方法，在小鼠动脉粥样斑块模型上，A、验证斑块内新生滋养血管与斑块的稳定性相关；B、探索选择性毁损斑块内新生滋养血管的适宜超声能量和条件及其物理效应；C、评价超声联合微泡治疗易损斑块的有效性和可行性及其病理机制，以期发展出一种有效、安全的治疗易损斑块的新方法。

稳定和逆转易损斑块干预治疗研究是目前的热点。研究显示：斑块内新生滋养血管与易损性密切相关，表明斑块内血管新生是治疗易损斑块的新靶点，然而抑制血管新生药物的治疗缺乏靶向性，其全身毒副作用严重限制了其临床应用。超声联合微泡所致的空化效应可以对血管壁产生直接和局部的物理损伤效应，无全身毒副作用。我们前期已经证实低能超声联合微泡能选择性毁损肿瘤新生血管并缩小肿瘤体积改善携瘤小鼠生存率。本项目的研究结果表明：超声联合微泡可以选择性毁损斑块内的新生血管逆转和稳定易损斑块。我们在ApoE-/-小鼠构建的动脉易损斑块模型上证实斑块内新生血管数目与易损斑块稳定性呈负相关， 3.0MPa声压的超声联合微泡是选择性毁损斑块内新生血管的最佳超声能量条件。我们进一步探讨了超声联合微泡干预逆转和稳定易损斑块的有效性和可行性，以及斑块内新生血管减少后易损斑块趋向稳定和逆转的病理机制，结果表明：超声联合微泡干预可以选择性毁损斑块内的新生血管，通过减少斑块内出血和抑制炎症介质实现易损斑块的稳定。本项目的研究成果为超声联合微泡技术选择性毁损斑块内新生血管和其它有相似物理效应的干预技术提供理论和/或方法基础，超声联合微泡有望成为一种无创、有效可用于临床逆转和稳定易损斑块的新技术。