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(Circulation Research. 2005;97:115.)
© 2005 American Heart Association, Inc.

Molecular Medicine

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

From the Department of Medicine (I.A.K., T.M., D.A., P.U., J.R.J., V.N., D.B.P., J.G.N.G., A.D.V.), Division of Pulmonary and Critical Care Medicine, and Departments of Anesthesiology (L.H.R.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Dr Alexander D. Verin, 5200 Eastern Ave, MFL Bldg, Center Tower, Room 660, Baltimore, MD 21224. E-mail averin1{at}jhmi.edu

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_q and G_i2), 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 G_q 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.

Key Words: endothelial barrier • extracellular adenosine triphosphate • G protein • myosin phosphatase

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