The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature

• Published in: Nature communications Vol. 10; no. 1; pp. 5014 - 17
• Main Authors: Peghaire, C, Dufton, N P, Lang, M, Salles-Crawley, I I, Ahnström, J, Kalna, V, Raimondi, C, Pericleous, C, Inuabasi, L, Kiseleva, R, Muzykantov, V R, Mason, J C, Birdsey, G M, Randi, A M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Anticoagulants; Blood vessels; Cells, Cultured; Chromatin; Clonal deletion; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Exposure; Gene Expression Regulation; Hemorrhage; Homeostasis; Humans; Immunoprecipitation; Krueppel-like factor; Kruppel-Like Transcription Factors; Mice, Knockout; Microvasculature; Microvessels - cytology; Microvessels - metabolism; Promoter Regions, Genetic - genetics; Shear stress; Signal Transduction - genetics; Stress, Mechanical; Thromboembolism; Thrombomodulin; Thrombomodulin - genetics; Thrombomodulin - metabolism; Thrombosis; Thrombosis - genetics; Thrombosis - metabolism; Transcription factors; Transcriptional Regulator ERG - genetics; Transcriptional Regulator ERG - metabolism
• DOI: 10.1038/s41467-019-12897-w
• ISSN: 2041-1723

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 ) 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 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.