Molecular mechanisms involved in adenosine-induced endothelial cell barrier enhancement

Umapathy N Siddaramappa, Zheng Hong Fan, Evgeny Alexandrovich Zemskov, Irina B. Alieva, Stephen Matthew Black, Alexander Dmitriyevich Verin

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Extracellular adenosine is a physiologically relevant agonist released by various sources, including endothelial cells (EC) and activated platelets, with complex effects mediated via activation of P1 purinergic receptors. Adenosine-induced EC production of glutathione peroxidase1 and nitric oxide is recognized, and an anti-inflammatory mechanism has been described. Effects of extracellular adenosine on the pulmonary EC barrier function and vascular permeability, however, remain poorly characterized. In this study, we demonstrated the adenosine-induced rapid dose-dependent barrier enhancement in human pulmonary artery EC (HPAEC) as measured by an increase in transendothelial electrical resistance (TER). We have shown that HPAEC express only A2A and A2B adenosine receptors. Pharmacological and siRNA depletion studies indicate that A2A, but not A2B receptor activation is required for the adenosine-induced TER increase. Depletion of Gαs with a specific siRNA significantly attenuated the adenosine-induced TER response in HPAEC. In contrast, depletion of either Gαq or Gαi2 did not affect the adenosine-induced TER increase. This suggests that the adenosine-induced TER increase is cAMP-dependent. The adenosine-induced barrier enhancement effects were associated with a rearrangement of the EC F-actin component of the cytoskeleton, enhanced cell-surface presentation of cell-cell junctional protein VE-cadherin and an involvement of Myosin-light-chain phosphatase (MLCP). Our results suggest, for the first time, that adenosine regulates the EC barrier function via A2A receptors followed by Gαs engagement and is associated with cytoskeletal activation.

Original languageEnglish (US)
Pages (from-to)199-206
Number of pages8
JournalVascular Pharmacology
Volume52
Issue number5-6
DOIs
StatePublished - May 1 2010

Keywords

  • Anti-inflammation
  • Human pulmonary artery endothelial cells
  • Myosin-light-chain phosphatase
  • P1 receptor agonists

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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