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

Menglin Liu,Elizaveta V Benevolenskaya,Shiqin Xiong,Jalees Rehman,Lianghui Zhang,Glenn Marsboom,Ankit Jambusaria,Asrar B Malik,Peter T Toth

doi:10.1038/s41467-019-10134-y

Abstract

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.

Highlights

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration
We crossbred dual-fluorescent color mTmG reporter mice[28] with endothelial cells (ECs)-specific Scl-CreERT2 mice to generate an EC specific genetic lineage tracing mouse model. In these Scl-CreERT2 mice, the tamoxifen-inducible Cre recombinase is driven by a 5′ endothelial enhancer of the stem cell leukemia (Scl) locus that is restricted to the endothelium
Using 2-photon imaging of lungs in live mice, we observed that a sublethal concentration of the bacterial endotoxin lipopolysaccharide (LPS) i.p. (12 mg/kg), which induces severe inflammatory injury, produced acute and severe loss of EGFP+ (EGFP positive) ECs; this was followed by a period of gradual recovery over several days (Fig. 1b, Supplementary Videos 1 and 2)

Summary

Introduction

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. We show that the endothelial and hematopoietic developmental transcription factor Sox[17] promotes endothelial regeneration in the endotoxemia model of endothelial injury. We conclude that endotoxemia adaptively activates Sox[17] expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis. Little is known about the signaling mechanisms or cells responsible for endothelial regeneration following severe inflammatory injury[14,15,16]. In the present study, using a mouse endotoxemia model of inflammatory endothelial injury, we demonstrate that endothelial Sox[17] expression plays an obligatory role in normalizing the endothelium. Restoration of endothelial integrity is mediated by activation of Hypoxia inducible factor-1α (HIF-1α), upregulation of its target Sox[17], and subsequent downstream expression of Cyclin E1 which mediates endothelial regeneration

Methods

Results

Conclusion