Nature Medicine
10, 502 - 509 (2004)
Published online: 18 April 2004; | doi:10.1038/nm1037
Regulation of angiogenesis by tissue factor cytoplasmic domain signalingMattias Belting1, 7, Michael I Dorrell2, 7, Staffan Sandgren3, Edith Aguilar2, Jasimuddin Ahamed1, Andrea Dorfleutner1, 6, Peter Carmeliet4, Barbara M Mueller5, Martin Friedlander2
& Wolfram Ruf11
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 2
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 3
Biomedical Centre, C-13, Lund University, SE-221 84 Lund, Sweden. 4
Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium, B-3000. 5
Division of Cancer Biology, La Jolla Institute for Molecular Medicine, 4570 Executive Drive, San Diego, California 92121, USA. 6
Present address: The Mary Babb Randolph Cancer Center and the Department of Microbiology and Immunology, West Virginia University, Morgantown, West Virginia 26506, USA. 7
These authors contributed equally to this work.
Correspondence should be addressed to Martin Friedlander friedlan@scripps.edu or Wolfram Ruf ruf@scripps.eduHemostasis 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)-VIIa 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 (TF CT 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.
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