Disordered Purinergic Signaling Inhibits Pathological Angiogenesis in cd39/Entpd1-null Mice

Am J Pathol. 2007 Oct;171(4):1395-404. doi: 10.2353/ajpath.2007.070190. Epub 2007 Sep 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apyrase / genetics
  • Apyrase / metabolism*
  • Cell Adhesion
  • Cell Proliferation
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Gene Deletion
  • Integrin alphaVbeta3 / metabolism
  • Integrins / metabolism*
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Mutant Strains
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Protein Kinases / metabolism
  • Purines / metabolism*
  • Receptors, Purinergic P2 / metabolism
  • Signal Transduction

Substances

  • Antigens, CD
  • Integrin alphaVbeta3
  • Integrins
  • Purines
  • Receptors, Purinergic P2
  • Protein Kinases
  • Apyrase
  • CD39 antigen