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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2801-2809
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Differential catalytic properties and vascular topography of
murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and
NTPDase2 have implications for thromboregulation
Jean Sévigny,
Christian Sundberg,
Norbert Braun,
Olaf Guckelberger,
Eva Csizmadia,
Imrana Qawi,
Masato Imai,
Herbert Zimmermann, and
Simon C. Robson
From the Departments of Medicine and Pathology, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
Centre de recherche en Rhumatologie et Immunologie CHUQ,
Université Laval, Sainte-Foy, Québec, Canada; and
Biozentrum der JW Goethe-Universität, AK Neurochemie,
Zoologisches Institut, Frankfurt am Main, Germany.
Nucleoside triphosphate diphosphohydrolases (NTPDases) are a
recently described family of ectonucleotidases that differentially hydrolyze the  and  phosphate residues of extracellular
nucleotides. Expression of this enzymatic activity has the potential to
influence nucleotide P2 receptor signaling within the vasculature. We
and others have documented that NTPDase1 (CD39, 78 kd) hydrolyzes both
triphosphonucleosides and diphosphonucleosides and thereby terminates
platelet aggregation responses to adenosine diphosphate (ADP). In
contrast, we now show that NTPDase2 (CD39L1, 75 kd), a preferential
nucleoside triphosphatase, activates platelet aggregation by converting
adenosine triphosphate (ATP) to ADP, the specific agonist of
P2Y1 and P2Y12 receptors. We developed
specific antibodies to murine NTPDase1 and NTPDase2 and
observed that both enzymes are present in the cardiac vasculature;
NTPDase1 is expressed by endothelium, endocardium, and to a
lesser extent by vascular smooth muscle, while NTPDase2 is associated
with the adventitia of muscularized vessels, microvascular pericytes,
and other cell populations in the subendocardial space. Moreover,
NTPDase2 represents a novel marker for microvascular pericytes.
Differential expression of NTPDases in the vasculature suggests
spatial regulation of nucleotide-mediated signaling. In this
context, NTPDase1 should abrogate platelet aggregation and recruitment
in intact vessels by the conversion of ADP to adenosine monophosphate,
while NTPDase2 expression would promote platelet microthrombus
formation at sites of extravasation following vessel injury. Our data
suggest that specific NTPDases, in tandem with ecto-5'-nucleotidase,
not only terminate P2 receptor activation and trigger adenosine
receptors but may also allow preferential activation of
specific subsets of P2 receptors sensitive to ADP (eg,
P2Y1, P2Y3, P2Y12) and uridine diphosphate (P2Y6).
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