Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice

Zachary M. Huttinger, Michael W. Milks, Michael S. Nickoli, William L. Aurand, Lawrence C. Long, Debra G. Wheeler, Karen M. Dwyer, Anthony J.F. D'Apice, Simon C. Robson, Peter J. Cowan, Richard J. Gumina

Research output: Contribution to journalArticle

15 Scopus citations

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 IIb3, 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.

Original languageEnglish (US)
Pages (from-to)322-333
Number of pages12
JournalAmerican Journal of Pathology
Volume181
Issue number1
DOIs
StatePublished - Jul 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Huttinger, Z. M., Milks, M. W., Nickoli, M. S., Aurand, W. L., Long, L. C., Wheeler, D. G., Dwyer, K. M., D'Apice, A. J. F., Robson, S. C., Cowan, P. J., & Gumina, R. J. (2012). Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice. American Journal of Pathology, 181(1), 322-333. https://doi.org/10.1016/j.ajpath.2012.03.024