Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke
By D. Knowland, Ahmet Araç, Kohei J. Sekiguchi, Martin Hsu, S. Lutz, J. Perrino, G. Steinberg, B. Barres, A. Nimmerjahn, D. Agalliu. Neuron, 2014
607 citations recorded by the source corpus.
SUMMARY 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 novel 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 h post-stroke, TJs display profound structural defects only after two days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 h post-stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.
Subfields: Cell Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/917472daceab38be64696a7a969090f43ff7f39c
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In Cell Biology
In Neurology
- C. Iadecola
- J. Anrather
- Gabriela Constantin
- A. Prat
- Robert S. Pulido
- Roeben N. Munji
- D. Agalliu
- R. Daneman
Citations in the corpus
- Functional morphology of the blood-brain barrier in health and disease (2018, background): “These findings suggest that transcytosis impairs BBB function in the acute (within 6 h) phase of ischaemic stroke, whereas breakdown of TJs and increased paracellular permeability of CNS endothelium occurs in the late phase (24–48 h) following ischaemic stroke [62].”
- Immune responses to stroke: mechanisms, modulation, and therapeutic potential. (2020, background): “The BBB’s first opening, due to increased transcytosis, occurs within hours after cerebral ischemia (93).”
- Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions (2022, methodology): “This model was mostly used for studying blood-brain barrier disruption and inflammatory response in cerebral ischemia.(20,21) Besides MCAO model, photothrombosis model is also utilized to induce cerebral ischemia in both mice and rats.”
- The blood–brain barrier in health and disease: Important unanswered questions (2020, background): “…(Ben-Zvi et al., 2014; Daneman et al., 2010a; Sohet et al., 2015; Sauvageot and Stiles, 2002), delaying astrocytic contact with ECs does not affect barrier formation (Saunders et al., 2016), and laser ablation of astrocyte endfeet in adult mice does not induce BBB leakage (Kubotera et al., 2019).”
- The blood-brain barrier. (2015, background): “In addition, analysis in transgenic models has identified that there are stepwise alterations in the BBB, with an increase in transcytosis observed first followed by alterations in the TJs (Knowland et al. 2014).”