Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors

Abstract

Objective: von Willebrand factor (VWF) is acutely released from endothelial cells in response to numerous calcium-raising agents (e.g. thrombin, histamine) and cAMPraising agents (e.g. epinephrine, adenosine, vasopressin). In contrast, very few inhibitors of endothelial VWFsecretion have been described. The neurotransmitter dopamine is amodulator of exocytosis in several endocrine cells, and is possibly involved in the regulation of several endothelial cell functions. We therefore investigated the effect of dopamine on endothelial VWF secretion. Results: Dopamine, D2/D3- and D4-specific agonists inhibited histamine- but not thrombin-induced VWF secretion. Expression of dopamine D2, D3 and D4 receptors was demonstrated by reverse transcription polymerase chain reaction (RT-PCR) in both human aortic (HAEC) and umbilical vein (HUVEC) endothelial cells. D2-D4 agonists did not inhibit histamine-induced rise in [Ca2+]i: they inhibited histamine-induced secretion even in the absence of extracellular calcium. Thus, the dopamine effects are not mediated by [Ca2+]i-dependent signalling. D2/D3- and D4-specific agonists inhibited neither the rise in cAMP nor VWF secretion in response to epinephrine and adenosine, arguing against an effect on cAMP-mediated signalling. D1 andD5 receptors were not detected in HAEC or HUVEC by RT-PCR, and the D1/ D5-specific agonist SKF 38 393 failed to modulate VWF secretion, arguing against a role for these receptors in endothelial exocytosis. Conclusions: Dopamine inhibits his tamine- induced endothelial exocytosis by activating D2-D4 receptor, via a mechanism distinct from [Ca2+]i-or cAMPmediated signaling. In contrast, D1 and D5 receptors are not functionally expressed in cultured endothelial cells. Dopamine agonists may be useful as inhibitors of endothelial activation in inflammation and cardiovascular disease. © 2006 International Society on Thrombosis and Haemostasis.