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Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Nature Medicine volume 10, pages 502–509 (2004)Cite this article

Abstract

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)-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 (TFΔCT 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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Figure 1: Enhanced tumor growth and angiogenesis in TFΔCT mice.
Figure 2: Synergy of TF-VIIa complex and PDGF-BB in angiogenesis.
Figure 3: TF cytoplasmic domain suppresses PAR-2-dependent angiogenesis.
Figure 4: Accelerated developmental angiogenesis in TFΔCT mice.
Figure 5: Normal astrocyte morphology and pericyte recruitment in TFΔCT mice.
Figure 6: TF phosphorylation and PAR-2 expression in ocular neovascularization.

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Acknowledgements

We thank P. Tejada, A. Donner, and J. Royce for technical assistance; P. Andrade-Gordon for providing PAR-2-deficient mice; and G. Vlasuk for NAP-c2 and NAP-5. M.B. is a fellow of the Medical Faculty, Lund University, Sweden. M.I.D. was supported by Achievement Rewards for Collegiate Scientists. This work was funded by the National Heart Lung Blood Institute (HL-16411 and HL-60742 to W.R.), the National Cancer Institute (CA-85405 to B.M.M.), the National Eye Institute (EY-11254 to M.F.) and the Robert Mealey Program for the Study of Macular Degenerations (to M.F.).

Author information

Author notes

  1. Andrea Dorfleutner

    Present address: The Mary Babb Randolph Cancer Center and the Department of Microbiology and Immunology, West Virginia University, Morgantown, West Virginia, 26506, USA

  2. Mattias Belting and Michael I Dorrell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Mattias Belting, Jasimuddin Ahamed, Andrea Dorfleutner & Wolfram Ruf

  2. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Michael I Dorrell, Edith Aguilar & Martin Friedlander

  3. Biomedical Centre, C-13, Lund University, Lund, SE-221 84, Sweden

    Staffan Sandgren

  4. Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, B-3000, Belgium

    Peter Carmeliet

  5. Division of Cancer Biology, La Jolla Institute for Molecular Medicine, 4570 Executive Drive, San Diego, 92121, California, USA

    Barbara M Mueller

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Correspondence to Martin Friedlander or Wolfram Ruf.

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Belting, M., Dorrell, M., Sandgren, S. et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 10, 502–509 (2004). https://doi.org/10.1038/nm1037

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