Title

Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module

Authors

Roeben Nocon Munji, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Allison Luen Soung, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Geoffrey Aaron Weiner, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Fabien Sohet, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Bridgette Deanne Semple, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Alpa Trivedi, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Kayleen Gimlin, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Masakazu Kotoda, Department of Neurosurgery and Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Masaaki Korai, Department of Neurosurgery and Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Sidar Aydin, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Austin Batugal, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Anne Christelle Cabangcala, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
Patrick Georg Schupp, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Michael Clark Oldham, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Tomoki Hashimoto, Department of Neurosurgery and Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Linda J. Noble-Haeusslein, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Richard Daneman, Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA. Rdaneman@ucsd.edu.

Document Type

Article

Abstract

Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.

Medical Subject Headings

Animals; Biotin (metabolism); Blood-Brain Barrier (metabolism); Brain (metabolism); Brain Injuries, Traumatic (metabolism); Endothelial Cells (metabolism); Infarction, Middle Cerebral Artery; Kainic Acid; Mice; Mice, Transgenic; Multiple Sclerosis (chemically induced, metabolism); Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Permeability; Pertussis Toxin; Seizures (chemically induced, metabolism); Signal Transduction; Stroke (metabolism); Transcriptome (genetics)

Publication Date

11-1-2019

Publication Title

Nature neuroscience

E-ISSN

1546-1726

Volume

22

Issue

11

First Page

1892

Last Page

1902

PubMed ID

31611708

Digital Object Identifier (DOI)

10.1038/s41593-019-0497-x

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