Mfsd2a Attenuates Blood-Brain Barrier Disruption After Sub-arachnoid Hemorrhage by Inhibiting Caveolae-Mediated Transcellular Transport in Rats
Mfsd2a Attenuates Blood-Brain Barrier Disruption After Sub-arachnoid Hemorrhage by Inhibiting Caveolae-Mediated Transcellular Transport in Rats
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DOI：
10.1007/s12975-019-00775-y
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发表时间：
2020-10-01
影响因子：
6.9
通讯作者：
Chen, Gang
中科院分区：
文献类型：
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作者：
Zhao, Chongshun;Ma, Junwei;Chen, Gang
血脑屏障（BBB）破坏是蛛网膜下腔出血（SAH）致脑损伤的重要机制之一。过去的研究通常集中在内皮细胞的紧密连接上。然而，低的跨细胞转运水平在血脑屏障的正常功能中也起着重要作用。主要促进者超家族结构域2a （Mfsd2a）已被证明对维持正常血脑屏障至关重要。本研究旨在探讨Mfsd2a在SAH后血脑屏障破坏中的作用和机制。本研究采用交叉前池单次注射模型制造Sprague-Dawley大鼠实验性SAH。在我们的SAH模型中进行评估之前，我们使用特异性小干扰RNA和质粒下调和上调Mfsd2a的表达。采用Omega-3脂肪酸缺乏症饮食降低大鼠脑内DHA含量。Mfsd2a在SAH后表达水平显著下降，在SAH后72 h达到最低水平，随后逐渐恢复。在SAH后72 h，血脑屏障功能被破坏；Mfsd2a的上调逆转了这种损伤，而Mfsd2a的下调则加剧了这种损伤。这些影响主要是通过跨细胞运输介导的，特别是与紧密连接相比，小泡的变化。在停止omega-3脂肪酸供应后，Mfsd2a抑制小泡和保护血脑屏障的作用被消除。综上所述，Mfsd2a通过运输omega-3脂肪酸来抑制基于小泡的跨细胞转运，从而保护SAH后的血脑屏障。
Blood-brain barrier (BBB) disruption is one of the critical mechanisms of brain injury induced by subarachnoid hemorrhage (SAH). Past studies have often focused on the tight junctions of endothelial cells. However, low transcellular transport levels also play an important role in the normal functioning of the BBB. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be essential for the maintenance of the normal BBB. Our present study aimed to explore the roles and mechanisms of Mfsd2a in BBB disruption after SAH. In this study, a prechiasmatic cistern single-injection model was used to produce experimental SAH in Sprague-Dawley rats. Specific small-interfering RNA and plasmids were used to downregulate and upregulate the expression of Mfsd2a prior to assessments in our SAH model. Omega-3 fatty acid deficiency diet was used to reduce DHA in rat brain. The expression level of Mfsd2a decreased significantly after SAH and reached its lowest level at 72 h post-SAH, which then gradually recovered. At 72 h after SAH, BBB function was disrupted; upregulation of Mfsd2a reversed this damage, whereas downregulation of Mfsd2a exacerbated this damage. These effects were primarily mediated through transcellular transport, especially for changes in caveolae compared to those of tight junctions. After stopping the supply of omega-3 fatty acids, the effect of Mfsd2a on inhibition of caveolae and protection of the blood-brain barrier was eliminated. Taken together, Mfsd2a inhibits caveolae-based transcellular transport by transporting omega-3 fatty acids to protect the BBB after SAH.