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

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

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Aims: The cytoplasmic calcium concentration ([Ca2+]i) is an important factor determining the permeability of endothelial cell layers but little is known on the effect of [Ca2+]i dynamics on endothelial function. Here, we applied several conditions that trigger [Ca2+]i oscillations and cell-to-cell propagating Ca2+ waves, and determined the involvement of connexin channels and consequent effects on endothelial barrier function, in model systems based on immortalized and primary brain endothelial cells. Methods and Results: Exposure to low extracellular Ca2+ or bradykinin respectively triggered Ca2+ waves or oscillations that increased endothelial permeability in a [Ca2+]i-dependent manner. Both Ca2+ waves/oscillations and permeability alterations were inhibited by the connexin mimetic peptide Gap27. Ca2+ wave propagation involves gap junctional communication and opening of hemichannels but open hemichannels did not contribute as a permeability-increasing pathway. Ca2+ oscillations were inhibited by Cx37/43 knockdown and involved hemichannel opening as well as autocrine purinergic signaling. However, hemichannels were, as for Ca2+ waves, not the pathway of increased endothelial permeability. Exposure to ATP triggered, like bradykinin, Ca2+ oscillations but in contrast, those were not affected by Gap27 and did not disturb permeability. Conclusion: We conclude that connexin channels and purinergic signaling actively contribute to endothelial [Ca2+]i dynamics and are important to modulate endothelial permeability.
Original languageEnglish
Pages (from-to)1942-1957
Number of pages16
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Publication statusPublished - 1 Sep 2011

Keywords

  • connexin
  • calcium
  • blood brain barrier
  • endothelial cell

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