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

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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.
Keywords
RECEPTOR, MODEL, OSCILLATIONS, HEMICHANNELS, BRADYKININ, GLIAL-CELLS, ATP RELEASE, PROTEIN-KINASE, CELL MONOLAYERS, INTRACELLULAR CALCIUM, endothelium, calcium, brain ischemia, brain edema, blood-brain barrier

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Chicago
De Bock, Marijke, Maxime Culot, Nan Wang, Mélissa Bol, Elke Decrock, Elke De Vuyst, Anaelle Da Costa, et al. 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): 1942–1957.
APA
De Bock, Marijke, Culot, M., Wang, N., Bol, M., Decrock, E., De Vuyst, E., Da Costa, A., et al. (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), 1942–1957.
Vancouver
1.
De Bock M, Culot M, Wang N, Bol M, Decrock E, De Vuyst E, et al. Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood brain barrier permeability. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM. 2011;31(9):1942–57.
MLA
De Bock, Marijke, Maxime Culot, Nan Wang, et al. “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 (2011): 1942–1957. Print.
@article{1254124,
  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.},
  author       = {De Bock, Marijke and Culot, Maxime and Wang, Nan and Bol, M{\'e}lissa and Decrock, Elke and De Vuyst, Elke and Da Costa, Anaelle and Dauwe, Ine and Vinken, Mathieu and Simon, Alexander and Rogiers, Vera and De Ley, Gaspard and Evans, Howard and Bultynck, Geert and Dupont, Genevi{\`e}ve and Cecchelli, Rom{\'e}o and Leybaert, Luc},
  issn         = {0271-678X},
  journal      = {JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM},
  keyword      = {RECEPTOR,MODEL,OSCILLATIONS,HEMICHANNELS,BRADYKININ,GLIAL-CELLS,ATP RELEASE,PROTEIN-KINASE,CELL MONOLAYERS,INTRACELLULAR CALCIUM,endothelium,calcium,brain ischemia,brain edema,blood-brain barrier},
  language     = {eng},
  number       = {9},
  pages        = {1942--1957},
  title        = {Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood brain barrier permeability},
  url          = {http://dx.doi.org/10.1038/jcbfm.2011.86},
  volume       = {31},
  year         = {2011},
}

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