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Modulation of extracellular nucleotide‐mediated signaling by CD39/nucleoside triphosphate diphosphohydrolase‐1
Author(s) -
Robson Simon C.,
Enjyoji Keiichi,
Goepfert Christian,
Imai Masato,
Kaczmarek Elzbieta,
Lin Yuan,
Sévigny Jean,
Warny Michel
Publication year - 2001
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.1188
Subject(s) - purinergic receptor , biology , receptor , platelet activation , extracellular , adenosine , microbiology and biotechnology , p2 receptor , platelet , endocrinology , immunology , biochemistry
Extracellular nucleotide stimulation of purinergic/pyrimidinergic type‐2 (P2) receptors are components of platelet, endothelial cell (EC), and leukocyte activation that culminate in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (or NTPDase‐1), is highly expressed on quiescent endothelium, monocytes, and activated lymphocytes and therefore could influence these pathways. The potential of NTPDase‐1 to regulate P2‐receptor function in the vasculature has been established by our generation of cd39 ‐null mice. These mice exhibit a prothrombotic vascular phenotype ascribed to overexpression of tissue factor by endothelial cells following aberrant P2‐ (and potentially adenosine 2a/3) receptor activation. Mutant mice also show perturbations in hemostasis, secondary to platelet P2Y1‐receptor desensitization. In addition, administration of soluble NTPDase and/or induction of CD39 overexpression by adenoviral vectors consistently result in amelioration of vascular injury in several animal models tested. CD39 is also the major NTPDase expressed by monocyte‐macrophages (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 transendothelial migration of cd39 ‐null Mo are also related to aberrant P2‐receptor activation and have also been observed in vitro and in vivo. Overexpression of 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 activity and function in platelets, vascular, and immune cells. Drug Dev. Res. 53:193–207, 2001. © 2001 Wiley‐Liss, Inc.