Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Mattias Belting, Michael I. Dorrell, Staffan Sandgren, Edith Aguilar, Jasimuddin Ahamed, Andrea Dorfleutner, Peter Carmeliet, Barbara M. Mueller, Martin Friedlander, Wolfram Ruf*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

317 Scopus citations


Hemostasis initiates angiogenesis-dependent wound healing, and thrombosis is frequently associated with advanced cancer. Although activation of coagulation generates potent regulators of angiogenesis, little is known about how this pathway supports angiogenesis in vivo. Here we show that the tissue factor (TF)-VI la protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor-2 (PAR-2) signaling. In this context, the TF cytoplasmic domain negatively regulates PAR-2 signaling. Mice from which the TF cytoplasmic domain has been deleted (TFACT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular tissue from diabetic patients shows PAR-2 colocalization with phosphorylated TF specifically on neovasculature, suggesting that phosphorylation of the TF cytoplasmic domain releases its negative regulatory control of PAR-2 signaling in angiogenesis. Targeting the TF-VIIa signaling pathway may thus enhance the efficacy of angiostatic treatments for cancer and neovascular eye diseases.

Original languageEnglish (US)
Pages (from-to)502-509
Number of pages8
JournalNature Medicine
Issue number5
StatePublished - May 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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