OBJECTIVE The potential roles and mechanisms of pericytes in maintaining blood-brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models. METHODS Three hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA-/- mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects. RESULTS Our data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH. CONCLUSIONS This study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAH patients.

中文翻译：

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蛛网膜下腔出血后，亲环蛋白信号传导诱导周细胞相关的血脑屏障破坏。

目的周细胞在维持血脑屏障（BBB）完整性方面的潜在作用和机制尚不清楚，这将有助于制定蛛网膜下腔出血（SAH）的治疗策略。我们试图提供证据，证明在培养的周细胞和SAH模型中，周细胞在BBB破坏中的潜在作用以及CypA信号的可能参与和机制。方法使用253只成年雄性C57B6J小鼠，体重22至30 g，29只CypA-/-小鼠，30只CypA + / +（flox / flox）小鼠，和30只雄性新生C57B6J小鼠，研究CypA表达的时间过程在SAH后的周细胞中，CypA的内在功能和机制以及已知受体CD147是否介导这些作用。结果我们的数据表明SAH后细胞内CypA和CypA分泌均增加，并且可以激活CD147受体和下游NF-κB途径，以诱导MMP9表达和蛋白水解功能，以降解内皮紧密连接蛋白和基底膜。CypA充当其受体CD147的自分泌或旁分泌配体。尽管CypA可以被周细胞内吞，但是特定的内吞抑制剂氯丙嗪对MMP9的活化没有任何影响。但是，特异性敲除CD147可以逆转SAH后周细胞中CypA表达对BBB完整性的有害影响。结论这项研究首次证明CypA介导了SAH后周细胞对BBB破坏的有害作用，其可能由CD147 /NF-κB/ MMP9信号介导，和连接蛋白在大脑中的降解。通过针对CypA和周细胞，这项研究可能为SAH患者的治疗提供新的见解。