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(Circulation Research. 2008;103:1410.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Ecto-5' Nucleotidase (CD73)-Mediated Adenosine Generation and Signaling in Murine Cardiac Allograft Vasculopathy

Tomomi Hasegawa, Diane Bouïs, Hui Liao, Scott H. Visovatti, David J. Pinsky

From the Departments of Internal Medicine (T.H., D.B., H.L., S.H.V., D.J.P.) and Molecular and Integrative Physiology (D.J.P.) and the University of Michigan Cardiovascular Center (T.H., D.B., H.L., S.H.V., D.J.P.), University of Michigan, Ann Arbor.

Correspondence to David J. Pinsky, MD, 7220 C Medical Science Research Building III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail dpinsky{at}umich.edu

Ecto-5'-nucleotidase (CD73) catalyzes the terminal phosphohydrolysis of 5'-adenosine monophosphate and is widely expressed on endothelial cells where it regulates barrier function. Because it is also expressed on lymphocytes, we hypothesized that it modulates vascular immune regulation under homeostatic conditions and dysregulation under stress conditions such as cardiac allotransplantation. In a heterotopic cardiac allotransplantation model, CD73 deficiency in either donors or recipients resulted in decreased graft survival and the development of cardiac allograft vasculopathy, suggesting a contribution of CD73 on both graft-resident and circulating cells in vasculopathy pathogenesis. Vascular perturbations incited by lack of CD73 included loss of graft barrier function and diminished graft expression of the A_2B adenosine receptor (A_2BAR), with a concordant exacerbation of the acute inflammatory and immune responses. The importance of CD73 in modulating endothelial–lymphocyte interaction was further demonstrated in allomismatched in vitro coculture experiments. Either genetic deletion or pharmacological blockade of CD73 increased transendothelial lymphocyte migration and inflammatory responses, suggesting that CD73 plays a critical role to suppress transendothelial leukocyte trafficking through its enzymatic activity. In addition, antagonism of A_2BAR caused a significant increase in vascular leakage, and agonism of A_2BAR resulted in marked prolongation of graft survival and suppression of cardiac allograft vasculopathy development. These data suggest a new paradigm in which phosphohydrolysis of adenosine monophosphate by CD73 on graft-resident or circulating cells diminishes transendothelial leukocyte trafficking and mitigates inflammatory and immune sequelae of cardiac transplantation via the A_2BAR.

Key Words: ecto-5'-nucleotidase • adenosine receptor • cardiac allograft vasculopathy

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