Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2014-05, Vol.82 (3), p.603-617

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •Transgenic eGFP-Claudin5 mice enable continual time-lapse imaging of BBB TJs•TJ structural abnormalities are present at late but not early phases after stroke•EC endocytosis and transcytosis are both increased at early phases after stroke•Stroke impairs progressively the transcellular then paracellular endothelial barrier Knowland et al. generate a transgenic mouse line to image dynamic changes in tight junctions at the blood-brain barrier in vivo with two-photon microscopy and identify a mechanism of how endothelial cells respond to ischemic stroke with potential therapeutic implications.