Spreading depolarizations trigger caveolin-1–dependent endothelial transcytosis
Homa Sadeghian M.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorCorresponding Author
Baptiste Lacoste Ph.D.
The Ottawa Hospital Research Institute, Neuroscience Program, Ottawa, ON, Canada
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, ON, Canada
The University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
Department of Neurobiology, Harvard Medical School, Boston, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this authorTao Qin B.S.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorXavier Toussay Ph.D.
The Ottawa Hospital Research Institute, Neuroscience Program, Ottawa, ON, Canada
Search for more papers by this authorRoberto Rosa M.D.
Department of Neurobiology, Harvard Medical School, Boston, MA
Search for more papers by this authorFumiaki Oka M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorDavid Y. Chung M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorTsubasa Takizawa M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorCorresponding Author
Chenghua Gu Ph.D.
Department of Neurobiology, Harvard Medical School, Boston, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this authorCorresponding Author
Cenk Ayata M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this authorHoma Sadeghian M.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorCorresponding Author
Baptiste Lacoste Ph.D.
The Ottawa Hospital Research Institute, Neuroscience Program, Ottawa, ON, Canada
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, ON, Canada
The University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
Department of Neurobiology, Harvard Medical School, Boston, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this authorTao Qin B.S.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorXavier Toussay Ph.D.
The Ottawa Hospital Research Institute, Neuroscience Program, Ottawa, ON, Canada
Search for more papers by this authorRoberto Rosa M.D.
Department of Neurobiology, Harvard Medical School, Boston, MA
Search for more papers by this authorFumiaki Oka M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorDavid Y. Chung M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorTsubasa Takizawa M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Search for more papers by this authorCorresponding Author
Chenghua Gu Ph.D.
Department of Neurobiology, Harvard Medical School, Boston, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this authorCorresponding Author
Cenk Ayata M.D., Ph.D.
From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
Address correspondence to Baptiste Lacoste, Faculty of Medicine, Dept. of Cellular and Molecular Medicine, The Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa (ON) K1H 8M5, Canada. Tel: 613-562-5800 ext. 7124; E-mail: [email protected]; Chenghua Gu Harvard Medical School, Dept. of Neurobiology, Boston, MA 02115, U.S.A. Tel: 617-432-6364; Fax: 617-432-1639; E-mail: [email protected]; Cenk Ayata [Lead contact], Massachusetts General Hospital, Neurovascular Research Laboratory, 149 13th Street, 6408, Charlestown, MA 02129, U.S.A. Tel: 617-726-0821; Fax: 617-726-2547; E-mail: [email protected]Search for more papers by this author*These authors contributed equally to the work.
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.
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