Oestrogen ameliorates blood-brain barrier damage after experimental subarachnoid haemorrhage via the SHH pathway in male rats.
Oestrogen ameliorates blood-brain barrier damage after experimental subarachnoid haemorrhage via the SHH pathway in male rats.
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DOI：
10.1136/svn-2022-001907
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发表时间：
2023-06
影响因子：
5.9
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Zhang, Jie;Li, Haiying;Xu, Zhongmou;Lu, Jinxin;Cao, Chang;Shen, Haitao;Li, Xiang;You, Wanchun;Chen, Gang
性别差异影响蛛网膜下腔出血（SAH）的发生、进展和消退。雌激素在减轻SAH引起的脑血管痉挛和神经元凋亡中起保护作用。然而，雌激素是否影响血脑屏障（BBB）的完整性尚未得到充分的研究。在胃癌和肾上腺中，雌激素通过雌激素受体调节声刺猬（sonic hedgehog，SHH）信号通路，SHH信号通路通过上调紧密连接蛋白的表达在维持血脑屏障中发挥重要作用。本研究利用临床资料探讨雌激素与SHH信号通路的关系，并建立实验性SAH模型，探讨雌激素是否通过SHH通路改善SAH后血脑屏障损伤。通过患者的脑脊液（CSF）样本和基因型-组织表达数据库（GTEx）分析雌激素和SHH通路之间的相关性。然后，采用血管内穿孔法建立大鼠SAH模型，并给予雌激素、雌激素抑制剂和SHH信号通路抑制剂治疗。采用免疫印迹、免疫荧光和神经行为学实验分析雌激素对血脑屏障损伤的影响。ESLIA检测及相关性分析显示，患者脑脊液中雌激素水平与SHH通路呈正相关，GTEx基因相关性分析进一步证实了这一点。SHH在生理状态下主要表达于大鼠神经元和星形胶质细胞，雌激素预处理可上调SHH表达。在SAH模型中，雌激素预处理被发现逆转SAH诱导的SHH通路的减少，这被雌激素受体抑制剂抵消。此外，雌激素预处理减少SAH诱导的BBB损伤，脑水肿和神经功能障碍，这些都被SHH通路抑制剂消除。总之，我们在这里证明，雌激素预处理改善SAH后的脑损伤，至少部分通过SHH途径介导的血脑屏障保护。
Sex differences affect the occurrence, progression and regression of subarachnoid haemorrhage (SAH). Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH. However, whether oestrogen affects blood‒brain barrier (BBB) integrity has not been fully studied. Oestrogen has been found to regulate the sonic hedgehog (SHH) signalling pathway through the oestrogen receptor in gastric cancer and adrenal glands, and the SHH signalling pathway has an important role in maintaining the BBB by upregulating the expression of tight junction proteins. In this study, we investigated the relationship between oestrogen and the SHH signalling pathway using clinical data and established an experimental SAH model to explore whether oestrogen could ameliorate BBB damage after SAH through the SHH pathway. Correlations between oestrogen and the SHH pathway were analysed by patients’ cerebrospinal fluid (CSF) samples and the Genotype-Tissue Expression database (GTEx). Then, an experimental rat SAH model was established using the endovascular perforation method and treated with oestrogen, oestrogen inhibitors and SHH signalling pathway inhibitors. Then, the effects of oestrogen on BBB damage were analysed by western blot, immunofluorescence and neurobehavioural experiments. ESLIA detection and correlation analysis showed that oestrogen levels in patients’ CSF were positively correlated with the SHH pathway, which was further verified by GTEx gene-correlation analysis. SHH was found to be mainly expressed in neurons and astrocytes in rats under physiological conditions and was upregulated by oestrogen pretreatment. In the SAH model, oestrogen pretreatment was found to reverse SAH-induced decreases in the SHH pathway, which were counteracted by oestrogen receptor inhibitors. Furthermore, oestrogen pretreatment reduced SAH-induced BBB damage, brain oedema and neurological dysfunction, which were eliminated by SHH pathway inhibitors. In conclusion, we demonstrate here that oestrogen pretreatment ameliorates brain injury after SAH, at least in part through SHH pathway-mediated BBB protection.
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影响因子：
8.8
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