bFGF Protects Against Oxygen Glucose Deprivation/Reoxygenation-Induced Endothelial Monolayer Permeability via S1PR1-Dependent Mechanisms
bFGF Protects Against Oxygen Glucose Deprivation/Reoxygenation-Induced Endothelial Monolayer Permeability via S1PR1-Dependent Mechanisms
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DOI：
10.1007/s12035-017-0544-0
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发表时间：
2018-04-01
影响因子：
5.1
通讯作者：
Yu, Zhanyang
中科院分区：
文献类型：
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作者：
Lin, Li;Wang, Qingzhi;Yu, Zhanyang
血脑屏障（Blood-brain barrier，BBB）破坏是脑卒中、脑外伤等多种神经系统疾病的共同病理特征，是治疗这些疾病的重要靶点。碱性成纤维细胞生长因子（bFGF）作为FGF超家族成员，在血管生成、神经发生和神经元存活中发挥重要作用。我们最近发现，重组碱性成纤维细胞生长因子对小鼠创伤性脑损伤中血脑屏障破坏的保护作用。本研究通过检测缺氧缺糖再给氧（OGD/R）诱导的内皮细胞单层通透性，进一步探讨重组bFGF对血脑屏障保护作用的机制。我们发现，重组bFGF显着降低OGD/R诱导的原代人脑微血管内皮细胞（HBMEC）单层的通透性和保存OGD/R诱导的跨内皮电阻（TEER）的下降。Western blot和免疫细胞化学显示，bFGF显着拯救OGD/R诱导的连接蛋白ZO-1，occludin，和VE-钙粘蛋白的下调。我们进一步表明，bFGF的BBB保护作用是通过FGF受体1（FGFR 1）激活，因为FGFR 1抑制剂可以阻断这种保护作用。此外，我们发现bFGF的BBB保护作用至少部分是通过挽救OGD/R诱导的鞘氨醇-1-磷酸受体1（S1 PR 1）蛋白的下调，因为S1 PR 1抑制剂或SIPR 1小干扰RNA阻断了bFGF的BBB保护作用，而S1 PR 1激动剂单独具有与bFGF相当的BBB保护作用。这些发现将提高我们对bFGF对BBB的保护作用和机制的理解，并提出bFGF作为一种潜在的治疗剂，以防止神经系统疾病中的BBB损伤。
Blood-brain barrier (BBB) disruption is a common pathological feature of many neurological disorders including stroke and brain trauma, therefore is an important therapeutic target for treatment of these diseases. Basic fibroblast growth factor (bFGF) as a member of FGF superfamily plays critical roles in angiogenesis, neurogenesis, and neuron survival. We recently showed that recombinant bFGF protects against BBB disruption in traumatic brain injury in mice. In this study, we further investigated the mechanisms of recombinant bFGF in BBB protection by measuring the permeability of cultured endothelial cell monolayer induced by oxygen-glucose deprivation and reoxygenation (OGD/R). We found that recombinant bFGF significantly decreased OGD/R-induced permeability of primary human brain microvascular endothelial cell (HBMEC) monolayer and preserved OGD/R-induced decreases of trans-endothelial electrical resistance (TEER). Western blot and immunocytochemistry showed that bFGF significantly rescued OGD/R-induced downregulation of junction proteins ZO-1, occludin, and VE-cadherin. We further show that the BBB protective effect of bFGF is via FGF receptor 1 (FGFR1) activation as FGFR1 inhibitor can block this protection effect. Moreover, we revealed that the BBB protection effect of bFGF is at least partially through rescuing the OGD/R-induced downregulation of sphingosine-1- phosphate receptor 1 (S1PR1) protein, as S1PR1 inhibitor or SIPR1 small interfering RNA blocked the BBB protective effect of bFGF, whereas S1PR1 agonist alone has comparable BBB protection effect of bFGF. These findings will improve our understanding of the protective effect and mechanisms of bFGF on BBB and propose bFGF as a potential therapeutic agent against BBB damage in neurological disorders.