Alternatively spliced tissue factor induces angiogenesis through integrin ligation
- Y. W. van den Berga,
- L. G. van den Hengela,
- H. R. Myersa,
- O. Ayachia,
- E. Jordanovab,
- W. Rufc,
- C. A. Spekd,
- P. H. Reitsmaa,
- V. Y. Bogdanove and
- H. H. Versteega,1
- aThe Einthoven Laboratory for Experimental Vascular Medicine and
- bDepartment of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands;
- cDepartment of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;
- dCenter for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; and
- eDivision of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267
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Edited by Charles T. Esmon, Oklahoma Medical Research Foundation, Oklahoma City, OK, and approved September 25, 2009 (received for review May 15, 2009)
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-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.
Footnotes
- 1To whom correspondence should be addressed. E-mail: h.h.versteeg{at}lumc.nl
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Author contributions: Y.W.v.d.B., P.H.R., and H.H.V. designed research; Y.W.v.d.B., L.G.v.d.H., H.R.M., O.A., and E.J. performed research; W.R., C.A.S., and V.Y.B. contributed new reagents/analytic tools; Y.W.v.d.B., L.G.v.d.H., H.R.M., O.A., E.J., and H.H.V. analyzed data; and Y.W.v.d.B., P.H.R., V.Y.B., and H.H.V. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0905325106/DCSupplemental.
