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Purine Nucleotides Induce Regulated Secretion of von Willebrand
Factor: Involvement of Cytosolic Ca2+ and Cyclic
Adenosine Monophosphate-Dependent Signaling in Endothelial Exocytosis
Ulrich M. Vischer and
Claes B. Wollheim
From the Division de Biochimie Clinique, Department of Medicine,
Centre Médical Universitaire, Geneva, Switzerland.
von Willebrand factor (vWF) is stored and released from endothelial
secretory granules called Weibel-Palade (WP) bodies. Acute release can
be induced by thrombin, histamine, and other mediators of thrombosis or
inflammation. Their effect is thought to be mediated by an increase in
intracellular free calcium ([Ca2+]i).
Purine nucleotides such as adenosine triphosphate (ATP) and adenosine
diphosphate (ADP) are released from platelet dense granules and from
ischemic tissues and are important regulators of platelet function and
vascular tone. In the present study, we investigated whether they could
also induce exocytosis from cultured endothelial cells. ATP (1 to 100 µmol/L) induced a dose-related increase in vWF release, with a
2.3-fold maximal increase after 30 minutes. Similar responses were
observed with ADP. ATP induced calcium mobilization from intracellular
stores, an effect mimicked by 2-methylthio-ATP, a selective agonist for
P2y receptors. However, 2-methylthio-ATP-induced vWF release was only
43% of the ATP response. ATP-induced vWF release was also associated
with a twofold increase in cellular cyclic adenosine monophosphate
(cAMP) content, and was potentiated by 3-isobutyl-1-methylxanthine
([IBMX] added to increase cAMP levels by blocking cellular
phosphodiesterases) and 8-bromo-cAMP and inhibited by more than 50% by
Rp-8-CPT-cAMPS, a competitive protein kinase A inhibitor. Adenosine but
not 2-methylthio-ATP mimicked the ATP-induced increase in cAMP.
ATP-induced vWF release was partly inhibited by adenosine deaminase,
which degrades adenosine generated from ATP in the incubation medium.
Adenosine (1 to 100 µmol/L) failed to induce vWF release, but
potentiated the secretory response to 2-methylthio-ATP and thrombin
without modifying the calcium response to these agents. Our results
suggest that ATP/ADP can induce vWF release from endothelial cells via
dual activation of P2y and adenosine A2 receptors. ATP/ADP-induced
exocytosis could be involved in the regulation of thrombus formation
and ischemia-reperfusion injuries. Further, we provide evidence that a
receptor-mediated increase in cellular cAMP can potentiate the secretory response to calcium-mobilizing agents.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 118-127
© 1998 by The American Society of Hematology.
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