Spreading depolarizations trigger caveolin-1–dependent endothelial transcytosis

Homa Sadeghian, Baptiste Lacoste, Tao Qin, Xavier Toussay, Roberto Rosa, Fumiaki Oka, David Y. Chung, Tsubasa Takizawa, Chenghua Gu, Cenk Ayata

研究成果: Article

14 引用 (Scopus)

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Objective: Cortical spreading depolarizations (CSDs) are intense and ubiquitous depolarization waves relevant for the pathophysiology of migraine and brain injury. CSDs disrupt the blood–brain barrier (BBB), but the mechanisms are unknown. Methods: A total of six CSDs were evoked over 1 hour by topical application of 300 mM of KCl or optogenetically with 470 nm (blue) LED over the right hemisphere in anesthetized mice (C57BL/6 J wild type, Thy1-ChR2-YFP line 18, and cav-1 –/– ). BBB disruption was assessed by Evans blue (2% EB, 3 ml/kg, intra-arterial) or dextran (200 mg/kg, fluorescein, 70,000 MW, intra-arterial) extravasation in parietotemporal cortex at 3 to 24 hours after CSD. Endothelial cell ultrastructure was examined using transmission electron microscopy 0 to 24 hours after the same CSD protocol in order to assess vesicular trafficking, endothelial tight junctions, and pericyte integrity. Mice were treated with vehicle, isoform nonselective rho-associated kinase (ROCK) inhibitor fasudil (10 mg/kg, intraperitoneally 30 minutes before CSD), or ROCK-2 selective inhibitor KD025 (200 mg/kg, per oral twice-daily for 5 doses before CSD). Results: We show that CSD-induced BBB opening to water and large molecules is mediated by increased endothelial transcytosis starting between 3 and 6 hours and lasting approximately 24 hours. Endothelial tight junctions, pericytes, and basement membrane remain preserved after CSDs. Moreover, we show that CSD-induced BBB disruption is exclusively caveolin-1–dependent and requires rho-kinase 2 activity. Importantly, hyperoxia failed to prevent CSD-induced BBB breakdown, suggesting that the latter is independent of tissue hypoxia. Interpretation: Our data elucidate the mechanisms by which CSDs lead to transient BBB disruption, with diagnostic and therapeutic implications for migraine and brain injury.

元の言語English
ページ(範囲)409-423
ページ数15
ジャーナルAnnals of Neurology
84
発行部数3
DOI
出版物ステータスPublished - 2018 9 1
外部発表Yes

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

これを引用

Sadeghian, H., Lacoste, B., Qin, T., Toussay, X., Rosa, R., Oka, F., Chung, D. Y., Takizawa, T., Gu, C., & Ayata, C. (2018). Spreading depolarizations trigger caveolin-1–dependent endothelial transcytosis. Annals of Neurology, 84(3), 409-423. https://doi.org/10.1002/ana.25298