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(Circulation. 2001;104:3109.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Disordered Cellular Migration and Angiogenesis in cd39-Null Mice

Christian Goepfert, MD^*; Christian Sundberg, MD PhD^*; Jean Sévigny, PhD; Keiichi Enjyoji, PhD; Tomokazu Hoshi, MD PhD; Eva Csizmadia, MSc; Simon Robson, MD PhD

From the Departments of Medicine (C.G., J.S., K.E., T.H., E.C., S.R.) and Pathology (C.S.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.
*The first 2 authors contributed equally to this work.

Correspondence to Simon C. Robson, MD, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave, Boston, MA 02215. E-mail srobson{at}caregroup.harvard.edu

Background— Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 is the major ectonucleotidase of endothelial cells and monocytes and catalyzes phosphohydrolysis of extracellular nucleoside diphosphates (NDP) and triphosphates (NTP, eg, ATP and UTP). Deletion of cd39 causes perturbations in the hydrolysis of NTP and NDP in the vasculature. Activation of P2 receptors appears to influence endothelial cell chemotactic and mitogenic responses in vitro. Therefore, aberrant regulation of nucleotide P2 receptors may influence angiogenesis in cd39-null mice.

Methods and Results— In control mice, implanted Matrigel plugs containing growth factors were rapidly populated by monocyte/macrophages, endothelial cells, and pericytes, with the development of new vessels over days. In cd39-null mice, migrating cells were completely confined to the tissue-Matrigel interface in a clearly stratified manner. Absolute failure of new vessel ingrowth was consistently observed in the mutant mice. Linked to these findings, chemotaxis of cd39-null monocyte/macrophages to nucleotides was impaired in vitro. This abnormality was associated with desensitization of nucleotide receptor P2Y-mediated signaling pathways.

Conclusions— Our findings demonstrate a role for NTPDase1 and phosphohydrolysis of extracellular nucleotides in the regulation of the cellular infiltration and new vessel growth in a model of angiogenesis.

Key Words: adenosine • vessels • platelets • angiogenesis • endothelium

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