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Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Belting, Mattias LU ; Dorrell, Michael I; Sandgren, Staffan LU ; Aguilar, Edith; Ahamed, Jasimuddin; Dorfleutner, Andrea; Carmeliet, Peter; Mueller, Barbara M; Friedlander, Martin and Ruf, Wolfram (2004) In Nature Medicine 10(5). p.502-509
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 (TFDeltaCT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular... (More)
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 (TFDeltaCT 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
10
issue
5
pages
502 - 509
publisher
Nature Publishing Group
external identifiers
  • wos:000221242400028
  • pmid:15098027
  • scopus:2442700125
ISSN
1546-170X
DOI
10.1038/nm1037
language
English
LU publication?
yes
id
e118813f-64dd-4b60-b17a-055aea6bc0e5 (old id 122969)
date added to LUP
2007-07-10 11:14:34
date last changed
2017-10-22 04:35:01
@article{e118813f-64dd-4b60-b17a-055aea6bc0e5,
  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 (TFDeltaCT 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       = {Belting, Mattias and Dorrell, Michael I and Sandgren, Staffan and Aguilar, Edith and Ahamed, Jasimuddin and Dorfleutner, Andrea and Carmeliet, Peter and Mueller, Barbara M and Friedlander, Martin and Ruf, Wolfram},
  issn         = {1546-170X},
  language     = {eng},
  number       = {5},
  pages        = {502--509},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Regulation of angiogenesis by tissue factor cytoplasmic domain signaling},
  url          = {http://dx.doi.org/10.1038/nm1037},
  volume       = {10},
  year         = {2004},
}