The Journal of Experimental Medicine
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Published 6 December 2004. doi:10.1084/jem.20040915
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1395-1405
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Crucial Role for Ecto-5'-Nucleotidase (CD73) in Vascular Leakage during Hypoxia

Linda F. Thompson1, Holger K. Eltzschig2,4, Juan C. Ibla2,3, C. Justin Van De Wiele1, Regina Resta1, Julio C. Morote-Garcia2, and Sean P. Colgan2

1 Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
2 Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital
3 Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115
4 Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, D-72076, Germany

Address correspondence to Linda F. Thompson, Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Phone: (405) 271-7235; Fax: (405) 271-7128; email: Linda-Thompson{at}omrf.ouhsc.edu; or Sean P. Colgan, Dept. of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Thorn 704, 20 Shattuck St., Boston, MA 02115. Phone: (617) 278-0905; Fax: (617) 278-6957; email: colgan{at}zeus.bwh.harvard.edu

Extracellular adenosine has been widely implicated in adaptive responses to hypoxia. The generation of extracellular adenosine involves phosphohydrolysis of adenine nucleotide intermediates, and is regulated by the terminal enzymatic step catalyzed by ecto-5'-nucleotidase (CD73). Guided by previous work indicating that hypoxia-induced vascular leakage is, at least in part, controlled by adenosine, we generated mice with a targeted disruption of the third coding exon of Cd73 to test the hypothesis that CD73-generated extracellular adenosine functions in an innate protective pathway for hypoxia-induced vascular leakage. Cd73–/– mice bred and gained weight normally, and appeared to have an intact immune system. However, vascular leakage was significantly increased in multiple organs, and after subjection to normobaric hypoxia (8% O2), Cd73–/– mice manifested fulminant vascular leakage, particularly prevalent in the lung. Histological examination of lungs from hypoxic Cd73–/– mice revealed perivascular interstitial edema associated with inflammatory infiltrates surrounding larger pulmonary vessels. Vascular leakage secondary to hypoxia was reversed in part by adenosine receptor agonists or reconstitution with soluble 5'-nucleotidase. Together, our studies identify CD73 as a critical mediator of vascular leakage in vivo.

Key Words: adenosine • inflammation • edema • endothelium • knockout

C.J. Van De Wiele's present address is Dept. of Surgery, University of Oklahoma College of Medicine, Tulsa, OK 74135.

R. Resta's present address is Albany Regional Cancer Center, Amsterdam, NY 12010.

Abbreviations used in this paper: ANOVA, analysis of variance; APCP, {alpha},ß-methylene ADP; E-Ado, etheno-adenosine; E-AMP, etheno-AMP; ES, embryonic stem; NECA, 5'-(N-ethylcarboxamido)-adenosine; 5'-NT, 5'-nucleotidase.


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