Details

Autor(en) / Beteiligte

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

Titel

Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-11, Vol.106 (46), p.19497-19502

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.