Ultrasound-mediated microbubble destruction (UMMD) is a promising strategy to improve local drug delivery in specific tissues. However, acoustic cavitation can lead to harmful bioeffects in endothelial cells. We investigated the side effects of UMMD treatment on vascular function (contraction and relaxation) and endothelium integrity of ex vivo Wistar rat arteries. We used an isolated organ system to evaluate vascular responses and confocal microscopy to quantify the integrity and viability of endothelial cells. The arteries were exposed for 1–3 min to ultrasound at a 100 Hz pulse-repetition frequency, 0.5 MPa acoustic pressure, 50% duty cycle and 1%–5% v/v microbubbles. The vascular contractile response was not affected. The acetylcholine-dependent maximal relaxation response was reduced from 78% (control) to 60% after 3 min of ultrasound exposure. In arteries treated simultaneously with 1 min of ultrasound exposure and 1%, 2%, 3% or 5% microbubble concentration, vascular relaxation was reduced by 19%, 58%, 80% or 93%, respectively, compared with the control arteries. Fluorescent labeling revealed that apoptotic death, detachment of endothelial cells and reduced nitric oxide synthase phosphorylation are involved in relaxation impairment. We demonstrated that UMMD can be a safe technology if the correct ultrasound and microbubble parameters are applied. Furthermore, we found that tissue-function evaluation combined with cellular analysis can be useful to study ultrasound–microbubble–tissue interactions in the optimization of targeted endothelial drug delivery.

超声介导的微泡破坏 (UMMD) 是一种很有前景的策略，可以改善特定组织中的局部药物递送。然而，声空化会导致内皮细胞产生有害的生物效应。我们研究了血管功能（收缩和舒张）和内皮完整性UMMD治疗的副作用体外Wistar 大鼠动脉。我们使用离体器官系统来评估血管反应和共聚焦显微镜来量化内皮细胞的完整性和活力。动脉暴露于 100 Hz 脉冲重复频率、0.5 MPa 声压、50% 占空比和 1%–5% v/v 微泡的超声下 1-3 分钟。血管收缩反应不受影响。超声暴露 3 分钟后，乙酰胆碱依赖性最大松弛反应从 78%（对照）降低到 60%。在同时接受 1 分钟超声照射和 1%、2%、3% 或 5% 微泡浓度治疗的动脉中，与对照动脉相比，血管舒张分别降低了 19%、58%、80% 或 93%。荧光标记显示细胞凋亡，内皮细胞的脱离和一氧化氮合酶磷酸化的减少与松弛障碍有关。我们证明了如果应用正确的超声和微泡参数，UMMD 可以是一种安全的技术。此外，我们发现组织功能评估与细胞分析相结合可用于研究超声-微泡-组织相互作用以优化靶向内皮药物递送。