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Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

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.).

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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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