Signaling pathways involved in adenosine triphosphate-induced endothelial cell barrier enhancement

Irina A. Kolosova, Tamara Mirzapoiazova, Djanybek Adyshev, Peter Usatyuk, Lewis H. Romer, Jeffrey R. Jacobson, Viswanathan Natarajan, David B. Pearse, Joe G.N. Garcia, Alexander D. Verin

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Endothelial barrier dysfunction caused by inflammatory agonists is a frequent underlying cause of vascular leak and edema. Novel strategies to preserve barrier integrity could have profound clinical impact. Adenosine triphosphate (ATP) released from endothelial cells by shear stress and injury has been shown to protect the endothelial barrier in some settings. We have demonstrated that ATP and its nonhydrolyzed analogues enhanced barrier properties of cultured endothelial cell monolayers and caused remodeling of cell-cell junctions. Increases in cytosolic Ca2+ and Erk activation caused by ATP were irrelevant to barrier enhancement. Experiments using biochemical inhibitors or siRNA indicated that G proteins (specifically G αq and Gαi2), protein kinase A (PKA), and the PKA substrate vasodilator-stimulated phosphoprotein were involved in ATP-induced barrier enhancement. ATP treatment decreased phosphorylation of myosin light chain and specifically activated myosin-associated phosphatase. Depletion of Gαq with siRNA prevented ATP-induced activation of myosin phosphatase. We conclude that the mechanisms of ATP-induced barrier enhancement are independent of intracellular Ca2+, but involve activation of myosin phosphatase via a novel G-protein-coupled mechanism and PKA.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalCirculation research
Volume97
Issue number2
DOIs
StatePublished - Jul 22 2005
Externally publishedYes

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Keywords

  • Endothelial barrier
  • Extracellular adenosine triphosphate
  • G protein
  • Myosin phosphatase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Kolosova, I. A., Mirzapoiazova, T., Adyshev, D., Usatyuk, P., Romer, L. H., Jacobson, J. R., Natarajan, V., Pearse, D. B., Garcia, J. G. N., & Verin, A. D. (2005). Signaling pathways involved in adenosine triphosphate-induced endothelial cell barrier enhancement. Circulation research, 97(2), 115-124. https://doi.org/10.1161/01.RES.0000175561.55761.69