Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression
Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression
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DOI：
10.1038/s41380-022-01618-3
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发表时间：
2022-05-26
影响因子：
11
通讯作者：
Sohya, Kazuhiro
中科院分区：
文献类型：
--
作者：
Matsuno, Hitomi;Tsuchimine, Shoko;Sohya, Kazuhiro
一些证据表明，压力诱导与血脑屏障（BBB）通透性增加相关的神经血管功能障碍，这可能是将压力和精神疾病（包括重度抑郁症（MDD））联系起来的重要病理。然而，导致血脑屏障功能障碍与重度抑郁症病理生理相关的详细机制尚不清楚。在此，我们证明了血管内皮生长因子（VEGF）在应激诱导的血脑屏障功能障碍和抑郁样行为发展中的作用，VEGF是血管新生和血脑屏障通透性的关键介质。我们在BALB/c小鼠中建立了抑郁、慢性抑制应激（RS）动物模型，发现慢性应激小鼠血脑屏障通透性显著增加。免疫组织化学和电镜观察显示血脑屏障通透性的增加与脑内皮细胞的细胞旁和细胞间屏障改变有关。使用特异性单克隆抗体（DC101）对VEGF受体2 （VEGFR2）进行药理学抑制，可预防慢性rs诱导的血脑屏障通透性和快感缺乏行为。综上所述，这些结果表明VEGF/VEGFR2通过增加血脑屏障的通透性在抑郁症的发病机制中起着至关重要的作用，并且表明VEGFR2抑制可能是与血脑屏障功能障碍相关的MDD亚型的潜在治疗策略。
Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.