Alternatively spliced tissue factor induces angiogenesis through integrin ligation.
Proc Natl Acad Sci U S A
; 106(46): 19497-502, 2009 Nov 17.
Article
em En
| MEDLINE
| ID: mdl-19875693
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tromboplastina
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Processamento Alternativo
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Integrina alfa6beta1
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Integrina alfaVbeta3
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Neovascularização Patológica
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article