title: Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice.
abstract: Modulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/β(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.
authors.affiliation: Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH 43210-1252, USA.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Huttinger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Milks
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nickoli
authors.forename: William L
authors.initials: WL
authors.lastname: Aurand
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Long
authors.forename: Debra G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dwyer
authors.forename: Anthony J F
authors.initials: AJ
authors.lastname: d'Apice
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
mesh_terms: D000241:Adenosine / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001081:Apyrase / Q000378:metabolism / Q000502:physiology*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D002712:Chlorides; D005290:Ferric Compounds; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015703:Antigens, CD; D002712:Chlorides; D005290:Ferric Compounds; D018048:Receptors, Purinergic P2; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine; C024555:ferric chloride