Down-regulation of astrocytic sonic hedgehog by activation of endothelin ETB receptors: Involvement in traumatic brain injury-induced disruption of blood brain barrier in a mouse model
Down-regulation of astrocytic sonic hedgehog by activation of endothelin ETB receptors: Involvement in traumatic brain injury-induced disruption of blood brain barrier in a mouse model
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DOI：
10.1016/j.neuint.2021.105042
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发表时间：
2021-04-12
影响因子：
4.2
通讯作者：
Koyama, Yutaka
中科院分区：
文献类型：
--
作者：
Michinaga, Shotaro;Inoue, Ayana;Koyama, Yutaka
在成人大脑中，音刺猬作用于脑微血管内皮细胞以稳定血脑屏障。在脑损伤过程中，星形胶质细胞的音刺猬蛋白表达发生变化，这种变化已被证明会影响血脑屏障的通透性。然而，关于星形胶质细胞音刺猬产生的调节仍有许多未知之处。我们的研究结果表明，内皮素-1减少音刺猬mRNA的表达和细胞外蛋白的释放在小鼠脑培养的星形胶质细胞，但没有影响bEnd。3，小鼠脑微血管内皮细胞衍生的细胞系。内皮素-1对星形胶质细胞音刺猬蛋白表达的影响被ETB拮抗剂BQ 788抑制，但未被ETA拮抗剂FR 139317改变。在培养的星形胶质细胞和bEnd.3，内皮素-1并没有影响表达的音刺猬受体相关分子，补丁-1和smoothened。在创伤性脑损伤的动物模型中，对小鼠大脑的液压冲击损伤增加了sonic hedgehog、patched-1和smoothened的表达。重复施用BQ 788在流体撞击损伤后5天增强了音刺猬蛋白的表达。组织化学检查显示液压冲击伤后大脑胶质细胞酸性蛋白阳性星形胶质细胞表达音刺猬蛋白。外源性Sonic Hedgehog和BQ 788的施用抑制了由流体撞击损伤诱导的血管渗透性的指标伊文思蓝外渗。BQ 788对液压冲击损伤诱导的伊文思蓝外渗的影响可通过给予jervine（一种Sonic Hedgehog抑制剂）而降低。总之，这些结果表明，内皮素-1下调星形胶质细胞的音刺猬，促进破坏血脑屏障在创伤性脑损伤。
In the adult brain, sonic hedgehog acts on cerebral microvascular endothelial cells to stabilize the blood-brain barrier. The expression of sonic hedgehog by astrocytes is altered during brain injury, and this change has been shown to affect permeability of blood-brain barrier. However, much remains unknown about the regulation of astrocytic sonic hedgehog production. Our results showed that endothelin-1 reduced sonic hedgehog mRNA expression and extracellular protein release in mouse cerebral cultured astrocytes, but had no effect in bEnd.3, a mouse brain microvascular endothelial-derived cell line. The effect of endothelin-1 on astrocyte sonic hedgehog expression was suppressed by an ETB antagonist BQ788, but was unchanged by the ETA antagonist FR139317. In cultured astrocytes and bEnd.3, endothelin-1 did not affect the expression of the sonic hedgehog receptor-related molecules, patched-1 and smoothened. In an animal model of traumatic brain injury, fluid percussion injury on the mouse cerebrum increased the expression of sonic hedgehog, patched-1, and smoothened. Repeated administration of BQ788 enhanced sonic hedgehog expression at 5 days after fluid percussion injury. Histochemical examination revealed sonic hedgehog expression in glial fibrillary acidic protein-positive astrocytes in the cerebrum after fluid percussion injury. Administration of exogenous sonic hedgehog and BQ788 suppressed Evans blue extravasation, an indicator of blood vessel permeability, induced by fluid percussion injury. The effects of BQ788 on fluid percussion injury-induced Evans blue extravasation were reduced by the administration of jervine, a sonic hedgehog inhibitor. Altogether, these results suggest that endothelin-1 down-regulates astrocytic sonic hedgehog to promote disruption of the blood-brain barrier during traumatic brain injury.