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

doi:10.1038/nm1037

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

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

324 Scopus citations

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)-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 language	English (US)
Pages (from-to)	502-509
Number of pages	8
Journal	Nature Medicine
Volume	10
Issue number	5
DOIs	https://doi.org/10.1038/nm1037
State	Published - May 2004

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm1037

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title = "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)-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.",

author = "Mattias Belting and Dorrell, {Michael I.} and Staffan Sandgren and Edith Aguilar and Jasimuddin Ahamed and Andrea Dorfleutner and Peter Carmeliet and Mueller, {Barbara M.} and Martin Friedlander and Wolfram Ruf",

note = "Funding Information: 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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AU - Belting, Mattias

AU - Dorrell, Michael I.

AU - Sandgren, Staffan

AU - Aguilar, Edith

AU - Ahamed, Jasimuddin

AU - Dorfleutner, Andrea

AU - Carmeliet, Peter

AU - Mueller, Barbara M.

AU - Friedlander, Martin

AU - Ruf, Wolfram

N1 - Funding Information: 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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N2 - 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.

AB - 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.

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Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Abstract

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