Published online before print September 6, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070190

Accepted for publication June 27, 2007.

Article

Disordered Purinergic Signaling Inhibits Pathological Angiogenesis in Cd39/Entpd1-Null Mice

Shaun W. Jackson^*, Tomokazu Hoshi, Yan Wu^*, Xiaofeng Sun^*, Keiichi Enjyoji^*, Eva Cszimadia^*, Christian Sundberg, and Simon C. Robson^*@

From the Department of Medicine,* Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; the Second Department of Surgery, Asahikawa Medical College, Asahikawa, Hokkaido, Japan; and the Department of Medical Biochemistry and Microbiology, Biomedical Center and Children's Academic Hospital, Uppsala, Sweden

^@ To whom correspondence should be addressed. E-mail: srobson{at}bidmc.harvard.edu.

	Abstract

CD39/ecto-nucleoside triphosphate diphosphohydrolase-type-1 (ENTPD1) is the dominant vascular ecto-nucleotidase that catalyzes the phosphohydrolysis of extracellular nucleotides in the blood and extracellular space. This ecto-enzymatic process modulates endothelial cell, leukocyte, and platelet purinergic receptor-mediated responses to extracellular nucleotides in the setting of thrombosis and vascular inflammation. We show here that deletion of Cd39/Entpd1 results in abrogation of angiogenesis, causing decreased growth of implanted tumors and inhibiting development of pulmonary metastases. Qualitative abnormalities of Cd39-null endothelial cell adhesion and integrin dysfunction were demonstrated in vitro. These changes were associated with decreased activation of focal adhesion kinase and extracellular signaling-regulated kinase-1 and -2 in endothelial cells. Our data indicate novel links between CD39/ENTPD1, extracellular nucleotide-mediated signaling, and vascular endothelial cell integrin function that impact on angiogenesis and tumor growth.

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