Sox17 is required for endothelial regeneration following inflammation-induced vascular injury

• Published in: Nature communications Vol. 10; no. 1; p. 2126
• Main Authors: Liu, Menglin, Zhang, Lianghui, Marsboom, Glenn, Jambusaria, Ankit, Xiong, Shiqin, Toth, Peter T, Benevolenskaya, Elizaveta V, Rehman, Jalees, Malik, Asrar B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.05.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Blood vessels; Cell Differentiation; Cell Line; Cell Proliferation; Clonal deletion; Cyclin E - genetics; Cyclin E - metabolism; Disease Models, Animal; Endothelial cells; Endothelial Cells - physiology; Endothelium; Endothelium, Vascular - physiopathology; Endotoxemia; Endotoxemia - immunology; Endotoxemia - pathology; HEK293 Cells; HMGB Proteins - genetics; HMGB Proteins - metabolism; Homeostasis; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation; Injuries; Leukocytes; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - immunology; Lungs; Mice; Mice, Inbred C57BL; Mice, Transgenic; Normalizing; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Promoter Regions, Genetic - genetics; Regeneration; Regeneration - immunology; Signal Transduction - physiology; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10134-y

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. However, the mechanisms of endothelial regeneration remain poorly understood. Here we show that the endothelial and hematopoietic developmental transcription factor Sox17 promotes endothelial regeneration in the endotoxemia model of endothelial injury. Genetic lineage tracing studies demonstrate that the native endothelium itself serves as the primary source of endothelial cells repopulating the vessel wall following injury. We identify Sox17 as a key regulator of endothelial cell regeneration using endothelial-specific deletion and overexpression of Sox17. Endotoxemia upregulates Hypoxia inducible factor 1α, which in turn transcriptionally activates Sox17 expression. We observe that Sox17 increases endothelial cell proliferation via upregulation of Cyclin E1. Furthermore, endothelial-specific upregulation of Sox17 in vivo enhances lung endothelial regeneration. We conclude that endotoxemia adaptively activates Sox17 expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis.