Tissue Factor Pathway Inhibitor Blocks Angiogenesis via Its Carboxyl Terminus
| Autor: | Laurel S. Kleppe, Cheryl S. Mueske, Debabrata Mukhopadhyay, Ling Wang, Tyra A. Witt, Sinny Delacroix, Robert D. Simari, Eric W. Holroyd, Peter J. Psaltis, Katarina Larsen, Shuchong Pan, Adriana Harbuzariu, Thomas A. White |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Angiogenesis
Kinase insert domain receptor Biology Cell biology Vascular endothelial growth factor Neovascularization Endothelial stem cell Tissue factor chemistry.chemical_compound Tissue factor pathway inhibitor chemistry Immunology medicine Phosphorylation medicine.symptom Cardiology and Cardiovascular Medicine |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 32:704-711 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.111.243733 |
| Popis: | Objective— Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. Methods and Results— Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. Conclusion— These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|