on May 6, 2004
Published online before print May 6, 2004, doi: 10.1161/01.ATV.0000131267.13425.45
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Submitted on December 21, 2003
Accepted on March 15, 2004
Small GTP-Binding Protein Ral Is Involved in cAMP-Mediated Release of von Willebrand Factor From Endothelial Cells
Mariska G. Rondaij ;
From the Departments of Plasma Proteins (M.G.R., E.S., K.A.G., J.A.v.M., J.V.) and Experimental Immunohematology (J.P.t.K., P.L.H.), Sanquin Research at CLB, Amsterdam, the Netherlands; and the Department of Vascular Medicine (J.A.v.M.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
* To whom correspondence should be addressed. E-mail: J.Voorberg{at}sanquin.nl.
Objective--von Willebrand factor (vWF) is synthesized by endothelial cells and stored in specialized vesicles called Weibel-Palade bodies (WPBs). Recently, we have shown that the small GTP-binding protein Ral is involved in thrombin-induced exocytosis of WPBs. In addition to Ca2+-elevating secretagogues such as histamine and thrombin, release of WPB is also observed after administration of cAMP-raising substances such as epinephrine and vasopressin. In the present study, we investigated whether Ral is also involved in cAMP-mediated vWF release.
Methods and Results--Activation of Ral was observed 15 to 20 minutes after stimulation of endothelial cells with epinephrine, forskolin, or dibutyryl-cAMP. A cell-permeable peptide comprising the carboxy-terminal part of the Ral protein reduced both thrombin-induced and epinephrine-induced vWF secretion supporting a crucial role for Ral in this process. Furthermore, inhibition of protein kinase A by H-89 resulted in a marked reduction of vWF release and greatly diminished levels of GTP-Ral on stimulation with epinephrine. Activation of Ral was independent of the activation of Epac, a cAMP-regulated exchange factor for the small GTPases Rap1 and Rap2.
Conclusions--These results suggest that protein kinase A-dependent activation of Ral regulates cAMP-mediated exocytosis of WPB in endothelial cells.
Key words: Weibel-Palade bodies • von Willebrand factor • Ral • cAMP • endothelial cells
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