Title: Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability
Authors: De Bock, Marijke
Culot, Maxime
Wang, Nan
Bol, Mélissa
Decrock, Elke
De Vuyst, Elke
da Costa, Anaelle
Dauwe, Ine
Vinken, Mathieu
Simon, Alexander M
Rogiers, Vera
De Ley, Gaspard
Evans, William Howard
Bultynck, Geert
Dupont, Geneviève
Cecchelli, Romeo
Leybaert, Luc # ×
Issue Date: Sep-2011
Publisher: Lippincott Williams & Wilkins
Series Title: Journal of Cerebral Blood Flow and Metabolism vol:31 issue:9 pages:1942-1957
Article number: 10.1038/jcbfm.2011.86
Abstract: The cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) is an important factor determining the functional state of blood-brain barrier (BBB) endothelial cells but little is known on the effect of dynamic [Ca(2+)](i) changes on BBB function. We applied different agonists that trigger [Ca(2+)](i) oscillations and determined the involvement of connexin channels and subsequent effects on endothelial permeability in immortalized and primary brain endothelial cells. The inflammatory peptide bradykinin (BK) triggered [Ca(2+)](i) oscillations and increased endothelial permeability. The latter was prevented by buffering [Ca(2+)](i) with BAPTA, indicating that [Ca(2+)](i) oscillations are crucial in the permeability changes. Bradykinin-triggered [Ca(2+)](i) oscillations were inhibited by interfering with connexin channels, making use of carbenoxolone, Gap27, a peptide blocker of connexin channels, and Cx37/43 knockdown. Gap27 inhibition of the oscillations was rapid (within minutes) and work with connexin hemichannel-permeable dyes indicated hemichannel opening and purinergic signaling in response to stimulation with BK. Moreover, Gap27 inhibited the BK-triggered endothelial permeability increase in in vitro and in vivo experiments. By contrast, [Ca(2+)](i) oscillations provoked by exposure to adenosine 5' triphosphate (ATP) were not affected by carbenoxolone or Gap27 and ATP did not disturb endothelial permeability. We conclude that interfering with endothelial connexin hemichannels is a novel approach to limiting BBB-permeability alterations.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 June 2011; doi:10.1038/jcbfm.2011.86.
ISSN: 0271-678X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
× corresponding author
# (joint) last author

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