Calcium signaling is dispensable for receptor regulation of endothelial barrier function

Judith A. Stolwijk, Xuexin Zhang, Maxime Gueguinou, Wei Zhang, Khalid Matrougui, Christian Renken, Mohamed Trebak

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Endothelial barrier function is tightly regulated by plasma membrane receptors and is crucial for tissue fluid homeostasis; its dysfunction causes disease, including sepsis and inflammation. The ubiquitous activation of Ca 2+ signaling upon phospholipase C-coupled receptor ligation leads quite naturally to the assumption that Ca 2+ signaling is required for receptor-regulated endothelial barrier function. This widespread hypothesis draws analogy from smooth muscle and proposes the requirement of G protein-coupled receptor (GPCR)-generated Ca 2+ signaling in activating the endothelial contractile apparatus and generating interendothelial gaps. Notwithstanding endothelia being non-excitable in nature, the hypothesis of Ca 2+ -induced endothelial contraction has been invoked to explain actions of GPCR agonists that either disrupt or stabilize endothelial barrier function. Here, we challenge this correlative hypothesis by showing a lack of causal link between GPCR-generated Ca 2+ signaling and changes in human microvascular endothelial barrier function. We used three endogenous GPCR agonists: thrombin and histamine, which disrupt endothelial barrier function, and sphingosine-1-phosphate, which stabilizes barrier function. The qualitatively different effects of these three agonists on endothelial barrier function occur independently of Ca 2+ entry through the ubiquitous store-operated Ca 2+ entry channel Orai1, global Ca 2+ entry across the plasma membrane, and Ca 2+ release from internal stores. However, disruption of endothelial barrier function by thrombin and histamine requires the Ca 2+ sensor stromal interacting molecule-1 (STIM1), whereas sphingosine-1-phosphate-mediated enhancement of endothelial barrier function occurs independently of STIM1. We conclude that although STIM1 is required for GPCR-mediated disruption of barrier function, a causal link between GPCR-induced cytoplasmic Ca2+ increases and acute changes in barrier function is missing. Thus, the cytosolic Ca 2+ -induced endothelial contraction is a cum hoc fallacy that should be abandoned.

Original languageEnglish (US)
Pages (from-to)22894-22912
Number of pages19
JournalJournal of Biological Chemistry
Volume291
Issue number44
DOIs
StatePublished - Oct 28 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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