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Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Academic Article
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Overview

authors

  • van den Berg, Y. W.
  • van den Hengel, L. G.
  • Myers, H. R.
  • Ayachi, O.
  • Jordanova, E.
  • Ruf, Wolfram
  • Spek, C. A.
  • Reitsma, P. H.
  • Bogdanov, V. Y.
  • Versteeg, H. H.

publication date

  • November 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-alphaVbeta3 integrin interaction induces endothelial cell migration, whereas asTF-dependent formation of capillaries in vitro is dependent on alpha6beta1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to beta1 and beta3 integrin blockade and a TF-antibody that disrupts asTF-integrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.

subject areas

  • Alternative Splicing
  • Animals
  • Aorta
  • Capillaries
  • Cell Movement
  • Endothelium, Vascular
  • Factor V
  • Integrin alpha6beta1
  • Integrin alphaVbeta3
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic
  • Receptor, PAR-2
  • Thromboplastin
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Research

keywords

  • cancer
  • coagulation
  • endothelial cells
  • integrins
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Identity

PubMed Central ID

  • PMC2780792

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0905325106

PubMed ID

  • 19875693
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Additional Document Info

start page

  • 19497

end page

  • 19502

volume

  • 106

issue

  • 46

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