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)-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 (TF Delta CT 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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
authors.forename: Michael I
authors.initials: MI
authors.lastname: Dorrell
authors.forename: Staffan
authors.initials: S
authors.lastname: Sandgren
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Jasimuddin
authors.initials: J
authors.lastname: Ahamed
authors.forename: Andrea
authors.initials: A
authors.lastname: Dorfleutner
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Mueller
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D005128:Eye Diseases / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D044464:Receptor, PAR-2 / Q000502:physiology; D015398:Signal Transduction; D013925:Thromboplastin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D044464:Receptor, PAR-2; D013925:Thromboplastin