Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-brain Barrier Breakdown in Stroke

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2014 Apr 22

PMID 24746419

Citations 327

Authors

Daniel Knowland

Ahmet Arac

Kohei J Sekiguchi

Martin Hsu

Sarah E Lutz

John Perrino

Gary K Steinberg

Ben A Barres

Axel Nimmerjahn

Dritan Agalliu

Affiliations

Soon will be listed here.

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.

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