Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Belting, Mattias; Dorrell, Michael I.; Sandgren, Staffan; Aguilar, Edith; Ahamed, Jasimuddin; Dorfleutner, Andrea; Carmeliet, Peter; Mueller, Barbara M.; Friedlander, Martin; Ruf, Wolfram

doi:10.1038/nm1037

Cited by 320 publications

(309 citation statements)

References 42 publications

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“…Indeed, it has been suggested that the TF cytoplasmic domain may be phosphorylated at Ser253 and Ser258 (50). Consequently, this may regulate cell signaling and many cellular events, such as NF-κB activation, proinflammatory cytokine production, leukocyte recruitment and reactive oxygen species production in monocytes (51,52). Furthermore, our data demonstrate that FVIIa-induced signaling in keratinocytes is direct and specific, and independent of subsequent generation of FXa and thrombin.…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 55%

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Ploplis

et al. 2010

Mol Med

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Skin keratinocytes express tissue factor (TF) and are highly associated with skin wound healing. Although it has been demonstrated that perivascular TF expression in granulation tissue formed after dermal injury is downregulated during healing, studies of the mechanism of factor (F) VII, a TF ligand, in skin wound healing are lacking. We reported the use of a dermal punch model to demonstrate that low-expressing FVII mice (~1% of wild type [WT]) exhibited impaired skin wound healing compared with WT controls. These low-FVII mice showed defective reepithelialization and reduced inflammatory cell infiltration at wound sites. This attenuated reepithelialization was associated with diminished expression of the transcription factor early growth response 1 (Egr-1). In vitro, Egr-1 was shown to be essential for the FVIIa-induced regulation of keratinocyte migration and inflammation. Both Egr-1 upregulation and downstream inflammatory cytokine appearance in keratinocytes depended on FVIIa/TF/protease-activated receptor 2 (PAR-2)-induced signaling and did not require subsequent generation of FXa and thrombin. The participation of Egr-1 in FVIIa-mediated regulation of keratinocyte function was confirmed by use of Egr-1-deficient mice, wherein a significant delay in skin wound healing after injury was observed, relative to WT mice. The results from these studies demonstrate an in vivo mechanistic relationship between FVIIa, Egr-1 and the inflammatory response in keratinocyte function during the wound healing process.

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Section: R E S E a R C H A R T I C L Ementioning

confidence: 55%

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Ploplis

et al. 2010

Mol Med

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“…9 However, recent studies have provided clear evidence for relevant thrombin-independent, TF-mediated PAR signaling in angiogenesis in vivo. 27 In this context, the TF-dependent signaling occurs either by the TF-FVIIa protease complex specifically through PAR2 28,29 or by Role of tissue factor in hematological malignancies C López-Pedrera et al …”

Section: Differential Mechanisms Of Tf-induced Tumor Angiogenesismentioning

confidence: 99%

Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies

et al. 2006

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“…PARs are ubiquitously expressed in vascular and extravascular tissues, and TF-regulated PAR-2 signaling has been specifically linked to pathological angiogenesis of the retina (13,14). Although these and other studies have suggested a specific involvement of PARs in angiogenesis, the exact function of TF-initiated coagulation signaling in the context of hypoxia-driven tumor angiogenesis remains ill-defined.…”

mentioning

confidence: 99%

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Svensson

Kucharzewska

Christianson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein–coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up-regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2–mediated activation of hypoxic ECs. We show that PAR-2–dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2–dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation-dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cell-autonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa–dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2–mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors.

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Regulation of angiogenesis by tissue factor cytoplasmic domain signaling

Cited by 320 publications

References 42 publications

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

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