RESUMEN
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 (ErgiEC-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 ErgiEC-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.
Asunto(s)
Regulación de la Expresión Génica , Microvasos/metabolismo , Trombomodulina/metabolismo , Trombosis/metabolismo , Regulador Transcripcional ERG/metabolismo , Animales , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel , Ratones Noqueados , Microvasos/citología , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Estrés Mecánico , Trombomodulina/genética , Trombosis/genética , Regulador Transcripcional ERG/genéticaRESUMEN
Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and ß-catenin and is required for Ang1-dependent ß-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, ß-catenin and Notch signalling to promote vascular stability.
