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

Marijke De Bock, Maxime Culot, Nan Wang, Mélissa Bol, Elke Decrock, Elke De Vuyst, Anaelle Da Costa, Ine Dauwe, Mathieu Vinken, Alex Simon, Vera Rogiers, Gaspard De Ley, William Howard Evans, Geert Bultynck, Geneviève Dupont, Romeo Cecchelli, Luc Leybaert

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 [Ca 2+]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.

Original languageEnglish (US)
Pages (from-to)1942-1957
Number of pages16
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Connexins
Blood-Brain Barrier
Permeability
Bradykinin
Calcium
Brain
Carbenoxolone
Endothelial Cells
Adenosine Triphosphate
Peptides
Coloring Agents

Keywords

  • Blood-brain barrier
  • brain edema
  • brain ischemia
  • calcium
  • endothelium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

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, Alex; Rogiers, Vera; De Ley, Gaspard; Evans, William Howard; Bultynck, Geert; Dupont, Geneviève; Cecchelli, Romeo; Leybaert, Luc.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 31, No. 9, 09.2011, p. 1942-1957.

Research output: Contribution to journalArticle

De Bock, M, Culot, M, Wang, N, Bol, M, Decrock, E, De Vuyst, E, Da Costa, A, Dauwe, I, Vinken, M, Simon, A, Rogiers, V, De Ley, G, Evans, WH, Bultynck, G, Dupont, G, Cecchelli, R & Leybaert, L 2011, 'Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability', Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 9, pp. 1942-1957. https://doi.org/10.1038/jcbfm.2011.86
De Bock, Marijke ; Culot, Maxime ; Wang, Nan ; Bol, Mélissa ; Decrock, Elke ; De Vuyst, Elke ; Da Costa, Anaelle ; Dauwe, Ine ; Vinken, Mathieu ; Simon, Alex ; Rogiers, Vera ; De Ley, Gaspard ; Evans, William Howard ; Bultynck, Geert ; Dupont, Geneviève ; Cecchelli, Romeo ; Leybaert, Luc. / Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability. In: Journal of Cerebral Blood Flow and Metabolism. 2011 ; Vol. 31, No. 9. pp. 1942-1957.
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AU - Simon, Alex

AU - Rogiers, Vera

AU - De Ley, Gaspard

AU - Evans, William Howard

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N2 - 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 [Ca 2+]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.

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