Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.
Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.
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DOI：
10.1007/s00401-016-1551-3
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发表时间：
2016-05
影响因子：
12.7
通讯作者：
Reiss Y
中科院分区：
文献类型：
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作者：
Gurnik S;Devraj K;Macas J;Yamaji M;Starke J;Scholz A;Sommer K;Di Tacchio M;Vutukuri R;Beck H;Mittelbronn M;Foerch C;Pfeilschifter W;Liebner S;Peters KG;Plate KH;Reiss Y
中枢神经系统的稳态是由血脑屏障（BBB）维持的。血管生成素（ang1 / ang2）作为拮抗分子调节血管生成、血管稳定性、血管通透性和淋巴完整性。然而，血管生成素/Tie2信号在血脑屏障中的确切作用尚不清楚。我们研究了Ang-2对野生型和功能获得型（GOF）小鼠血脑屏障通透性的影响，发现Ang-2在体外和体内均能增加血脑屏障通透性。对ang2 - GOF小鼠脑内皮细胞的表达分析显示，紧密/粘附连接分子下调，小泡蛋白-1（一种与囊泡通透性相关的分子）升高。免疫组织化学显示Ang-2 GOF小鼠的周细胞覆盖减少，电镜分析也证实了这一点，内皮细胞连接缺陷，囊泡增加，糖萼减少/破坏。这些结果表明，Ang-2通过细胞旁和细胞外途径介导通透性。在中风患者中，Ang-2水平上调，这是一种与血脑屏障破坏相关的脑血管疾病。在小鼠实验脑卒中中，Ang-2 GOF导致梗死面积和血管通透性增加，提示Ang-2在脑卒中病理生理中的作用。通过使用血管内皮蛋白酪氨酸磷酸酶抑制剂激活Tie2信号来恢复通透性和卒中大小的增加，并且不依赖于ve -钙粘蛋白磷酸化。因此，我们确定Ang-2是内皮细胞来源的血脑屏障通透性调节剂。我们假设，针对Tie2信号的新疗法可能用于打开血脑屏障以增加中枢神经系统药物递送或在脑血管渗漏和脑水肿相关的神经系统疾病中收紧血脑屏障。本文的在线版本（doi:10.1007/s00401-016-1551-3）包含补充资料，仅供授权用户使用。
The homeostasis of the central nervous system is maintained by the blood–brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema. The online version of this article (doi:10.1007/s00401-016-1551-3) contains supplementary material, which is available to authorized users.