Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis.

Abstract:

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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Sadeghian H,Lacoste B,Qin T,Toussay X,Rosa R,Oka F,Chung DY,Takizawa T,Gu C,Ayata C

doi

10.1002/ana.25298

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

409-423

issue

3

eissn

0364-5134

issn

1531-8249

journal_volume

84

pub_type

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