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Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain
David J. Pinsky, … , Aaron J. Marcus, Charles R. Maliszewski
David J. Pinsky, … , Aaron J. Marcus, Charles R. Maliszewski
Published April 15, 2002
Citation Information: J Clin Invest. 2002;109(8):1031-1040. https://doi.org/10.1172/JCI10649.
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Categories: Article Vascular biology

Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain

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Abstract

Endothelial CD39 metabolizes ADP released from activated platelets. Recombinant soluble human CD39 (solCD39) potently inhibited ex vivo platelet aggregation in response to ADP and reduced cerebral infarct volumes in mice following transient middle cerebral artery occlusion, even when given 3 hours after stroke. Postischemic platelet and fibrin deposition were decreased and perfusion increased without increasing intracerebral hemorrhage. In contrast, aspirin did not increase postischemic blood flow or reduce infarction volume, but did increase intracerebral hemorrhage. Mice lacking the enzymatically active extracellular portion of the CD39 molecule were generated by replacement of exons 4–6 (apyrase-conserved regions 2–4) with a PGKneo cassette. Although CD39 mRNA 3′ of the neomycin cassette insertion site was detected, brains from these mice lacked both apyrase activity and CD39 immunoreactivity. Although their baseline phenotype, hematological profiles, and bleeding times were normal, cd39–/– mice exhibited increased cerebral infarct volumes and reduced postischemic perfusion. solCD39 reconstituted these mice, restoring postischemic cerebral perfusion and rescuing them from cerebral injury. These data demonstrate that CD39 exerts a protective thromboregulatory function in stroke.

Authors

David J. Pinsky, M. Johan Broekman, Jacques J. Peschon, Kim L. Stocking, Tomoyuki Fujita, Ravichandran Ramasamy, E. Sander Connolly Jr., Judy Huang, Szilard Kiss, Yuan Zhang, Tanvir F. Choudhri, Ryan A. McTaggart, Hui Liao, Joan H.F. Drosopoulos, Virginia L. Price, Aaron J. Marcus, Charles R. Maliszewski

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Figure 1

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Ex vivo aggregation of cd39+/+ murine platelets. Following administratio...
Ex vivo aggregation of cd39+/+ murine platelets. Following administration of saline vehicle, solCD39 (4 mg/kg), or aspirin (5 mg/kg), platelets were stimulated with 10 μM ADP (a), 2.5 μg/ml collagen (b), or 0.1 mM sodium arachidonate (c). SolCD39 treatment yielded aggregation curves that returned to baseline following stimulation with all three agonists. Aspirin treatment resulted in this pattern only when arachidonate was the agonist.
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