Alternatively spliced tissue factor induces angiogenesis through integrin ligation

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

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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 as TF-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-αVβ3 integrin interaction induces endothelial cell migration, whereas asTF-dependent formation of capillaries in vitro is dependent on α6β1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to β1 and β3 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.

Original languageEnglish
Pages (from-to)19497-19502
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - 17 Nov 2009
Externally publishedYes

Keywords

  • Cancer
  • Coagulation
  • Endothelial cells
  • Integrins

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