Modulation of extracellular nucleotide-mediated signaling by CD39/nucleoside triphosphate diphosphohydrolase-1

Extracellular nucleotide stimulation of purinergic/pyrimidinergic type-2 (P 2) receptors are components of platelet, endothelial cell (EC), and leukocy te activation that culminate in vascular thrombosis and inflammation in viv o. CD39, the prototype nucleoside triphosphate diphosphohydrolase (or NTPDa se-1), is highly expressed on quiescent endothelium, monocytes, and activat ed lymphocytes and therefore could influence these pathways. The potential of NTPDase-1 to regulate P2-receptor function in the vasculature has been e stablished by our generation of cd39-null mice. These mice exhibit a prothr ombotic vascular phenotype ascribed to overexpression of tissue factor by e ndothelial cells following aberrant P2- (and potentially adenosine 2a/3) re ceptor activation. Mutant mice also show perturbations in hemostasis, secon dary to platelet P2Y1-receptor desensitization. In addition, administration of soluble NTPDase and/or induction of CD39 overexpression by adenoviral v ectors consistently result in amelioration of vascular injury in several an imal models tested. CD39 is also the major NTPDase expressed by monocyte-ma crophages (Mo). Upregulation of tissue factor expression by Mo in vitro and alterations in splenic populations in vivo have been observed in cd39-null mice. Paradoxical inhibition of integrin-mediated adhesion and transendoth elial migration of cd39-null Mo are also related to aberrant P2-receptor ac tivation and have also been observed in vitro and in vivo. Overexpression o f CD39 following infection with recombinant adenoviral vectors also blocks LPS-induced ATP secretion and inhibits IL-1 release in vitro. These studies confirm a role for CD39 in the differential regulation of P2-receptor acti vity and function in platelets, vascular, and immune cells. (C) 2001 Wiley- Liss, Inc.