| Autor: |
Peghaire C; National Heart and Lung Institute, Imperial College London, London, UK., Dufton NP; National Heart and Lung Institute, Imperial College London, London, UK., Lang M; National Heart and Lung Institute, Imperial College London, London, UK., Salles-Crawley II; Centre for Haematology, Hammersmith Hospital Campus, Imperial College London, London, UK., Ahnström J; Centre for Haematology, Hammersmith Hospital Campus, Imperial College London, London, UK., Kalna V; National Heart and Lung Institute, Imperial College London, London, UK., Raimondi C; National Heart and Lung Institute, Imperial College London, London, UK., Pericleous C; National Heart and Lung Institute, Imperial College London, London, UK., Inuabasi L; National Heart and Lung Institute, Imperial College London, London, UK., Kiseleva R; Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, USA., Muzykantov VR; Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, USA., Mason JC; National Heart and Lung Institute, Imperial College London, London, UK., Birdsey GM; National Heart and Lung Institute, Imperial College London, London, UK., Randi AM; National Heart and Lung Institute, Imperial College London, London, UK. a.randi@imperial.ac.uk. |
| Abstrakt: |
Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (Erg iEC-KO ) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In Erg iEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS. |
