Disordered purinergic signaling inhibits pathological angiogenesis in cd39/Entpd1-null mice.
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.
Jackson
Shaun W
SW
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Hoshi
Tomokazu
T
Wu
Yan
Y
Sun
Xiaofeng
X
Enjyoji
Keiichi
K
Cszimadia
Eva
E
Sundberg
Christian
C
Robson
Simon C
SC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction