Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke

Daniel Knowland; Ahmet Arac; Kohei J Sekiguchi; Martin Hsu; Sarah E Lutz; John Perrino; Gary K Steinberg; Ben A Barres; Axel Nimmerjahn; Dritan Agalliu

doi:10.1016/j.neuron.2014.03.003

Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke

Neuron. 2014 May 7;82(3):603-17. doi: 10.1016/j.neuron.2014.03.003. Epub 2014 Apr 17.

Authors

Affiliations

¹ Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
² Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, University of California, Irvine, Orange, CA 92868, USA.
³ Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92037, USA.
⁴ Electron Microscopy Facility, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: animmerj@salk.edu.
⁸ Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA. Electronic address: dagalliu@uci.edu.

Abstract

Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / metabolism*
Blood-Brain Barrier / pathology*
Blood-Brain Barrier / ultrastructure
Endothelial Cells / metabolism
Endothelial Cells / pathology
Endothelial Cells / ultrastructure
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Stroke / metabolism*
Stroke / pathology*
Tight Junctions / metabolism
Tight Junctions / pathology
Transcytosis / physiology*

Abstract

Publication types

MeSH terms

Grants and funding