The Role of Caveolin-1 in Blood-Brain Barrier Disruption Induced by Focused Ultrasound Combined with Microbubbles
The Role of Caveolin-1 in Blood-Brain Barrier Disruption Induced by Focused Ultrasound Combined with Microbubbles
复制标题
Caveolin-1在聚焦超声联合微泡诱导血脑屏障破坏中的作用
DOI：
10.1007/s12031-011-9629-9
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发表时间：
2012-03-01
影响因子：
3.1
通讯作者：
Cheng, Yuan
中科院分区：
文献类型：
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作者：
Deng, Jinmu;Huang, Qin;Cheng, Yuan
本研究旨在确定应用聚焦超声(FUS)结合微泡破坏大鼠血脑屏障(BBB)是否会导致小窝密度和/或结构蛋白小窝-1表达的变化。为此，采用了两种方法。首先，利用增强磁共振成像技术，记录我们特定的FUS参数和微泡剂量对血脑屏障的破坏特征，并确定治疗后血脑屏障通透性最强的时间。其次，单独用FUS或微泡处理大鼠，或两者都不用，并结合伊文思蓝(EB)血脑屏障通透性分析、链霉亲和素-过氧化物酶(SP)免疫组织化学、Western印迹和透射电子显微镜(TEM)检测在先前确定的BBB最通透性的时间点小窝密度和小窝蛋白-1表达的变化。第一组研究表明，我们的特定FUS参数和微泡剂量能够诱导大鼠短暂的、靶向的和可逆的BBB开放，并且FUS和微泡处理1h后的BBB通透性最强。在第二组实验中，SP免疫组织化学、免疫印迹和透射电子显微镜的结果相结合，显示小凹和小窝-1主要定位于所有大鼠的脑微血管内皮细胞，并且小窝-1在FUS和微泡处理的大鼠中表达最高。总之，FUS结合一定剂量的微泡可以通过上调小窝蛋白-1的表达水平从而提高小窝的数量，从而通过小窝介导的跨细胞途径增强血脑屏障的通透性。这种小窝蛋白-1介导的跨细胞转运途径可能与其他转运途径协同作用，诱导血脑屏障的开放。这项研究揭示了FUS结合微泡诱导血脑屏障瞬时、靶向和可逆开放的机制。
This research was designed to determine whether disrupting the blood-brain barrier (BBB) in rats by applying focused ultrasound (FUS) combined with microbubbles induced changes in the density of caveolae and/or the expression of the structural protein caveolin-1. To this end, two approaches were utilized. First, using enhanced magnetic resonance imaging, characteristics of BBB disruption induced by our specific FUS parameters and dose of microbubble were recorded, and the time after treatment when the BBB was the most permeable was determined. Second, rats were treated with FUS or microbubbles alone, both or neither, and a combination of Evans blue (EB) BBB permeability assays, streptavidin-peroxidase (SP) immunohistochemistry, western blot, and transmission electron microscopy (TEM) was employed to detect any changes in caveolae density and caveolin-1 expression at the previously determined time point when the BBB was the most permeable. The first set of studies revealed that our specific FUS parameters and dose of microbubbles were able to induce a transient, targeted, and reversible BBB opening in rats, and that the BBB was the most permeable 1 h after treatment with FUS and microbubbles. In the second set of experiments, the results of the SP immunohistochemistry, western blot, and TEM, taken together, revealed that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all of the rats regardless of treatment, and that caveolin-1 expression was highest in the rats treated with both FUS and microbubbles. In summary, treatment with FUS, in combination with a dose of microbubbles, can enhance BBB permeability through a caveolae-mediated transcellular approach by upregulating the expression level of caveolin-1 and, consequently, the amount of caveolae. This caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways to induce opening of the BBB. This research sheds light on the mechanism of a transient, targeted, and reversible opening of the BBB induced by FUS combined with microbubbles.