Adenosine 3’:5’-Cyclic Monophosphate Induces Regulated Secretion of Tissue-Type Plasminogen Activator and von Willebrand Factor from Cultured Human Endothelial Cells

Summary

The effect of compounds increasing intracellular adenosine 3’:5’-cyclic monophosphate [cAMP]_i levels (prostacyclin, isoproterenol, forskolin, cholera toxin), and of the cAMP analogs 8-bromo-cAMP and dibutyryl-cAMP, on the regulated secretion (acute release) of tissue-type plasminogen activator (tPA) and von Willebrand factor (vWF) was studied in cultured human umbilical vein endothelial cells (HUVEC).

Prostacyclin, isoproterenol and forskolin, which increased [cAMP]_i in HUVEC, and the cell-permeant cAMP analog 8-bromo-cAMP induced dose- and time-dependent secretion of tPA and vWF. The extent of vWF and tPA release correlated with [cAMP]_i, and was increased by the phosphodiesterase inhibitor isobutylmethylxanthine.

In contrast to thrombin, the cAMP-elevating agents did not increase the intracellular calcium concentration [Ca²⁺]_i in HUVEC. At sub-maximal concentrations, the effects of thrombin and prostacyclin were additive.

Our results show that an increase in [cAMP]_i resulted in regulated secretion (acute release) of tPA and vWF from HUVEC, without the concomitant increase in [Ca²⁺]_i which is, in HUVEC, essential for thrombin-induced regulated secretion to occur. cAMP-induced secretion represents a novel mechanism for causing regulated secretion of tPA and vWF from endothelial cells.

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