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Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability

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 and Leybaert, Luc 2011. Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability. Journal of Cerebral Blood Flow and Metabolism 31 (9) , pp. 1942-1957. 10.1038/jcbfm.2011.86

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Abstract

The cytoplasmic Ca2+ concentration ([Ca2+]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 [Ca2+]i changes on BBB function. We applied different agonists that trigger [Ca2+]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 [Ca2+]i oscillations and increased endothelial permeability. The latter was prevented by buffering [Ca2+]i with BAPTA, indicating that [Ca2+]i oscillations are crucial in the permeability changes. Bradykinin-triggered [Ca2+]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, [Ca2+]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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: blood–brain barrier, brain edema, brain ischemia, calcium, endothelium
Publisher: Lippincott, Williams & Wilkins
ISSN: 0271-678X
Last Modified: 17 Mar 2021 02:50
URI: https://orca.cardiff.ac.uk/id/eprint/30035

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