Abstract
Enhancing endothelial barrier integrity for the treatment of acute lung injury (ALI) is an emerging novel therapeutic strategy. Our previous studies have demonstrated the essential role of FoxM1 in mediating endothelial regeneration and barrier repair following lipopolysaccharide-induced lung injury. However, it remains unclear whether FoxM1 expression is sufficient to promote endothelial repair in experimental models of sepsis. Here, employing the FoxM1 transgenic (FoxM1 Tg) mice, we showed that transgenic expression of FoxM1 promoted rapid recovery of endothelial barrier function and survival in a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP). We observed lung vascular permeability was rapidly recovered and returned to levels similar to baseline at 48 h post-CLP challenge in FoxM1 Tg mice whereas it remained markedly elevated in WT mice. Lung edema and inflammation were resolved only in FoxM1 Tg mice at 24 h post-CLP. 5-bromo-2-deoxyuridine incorporation assay revealed a drastic induction of endothelial proliferation in FoxM1 Tg lungs at 24h post-CLP, correlating with early induction of expression of FoxM1 target genes essential for cell cycle progression. Additionally, deletion of FoxM1 in endothelial cells, employing the mouse model with endothelial cell-restricted disruption of FoxM1 (FoxM1 CKO) resulted in impaired endothelial repair following CLP challenge. Together, these data suggest FoxM1 expression in endothelial cells is necessary and sufficient to mediate endothelial repair and thereby promote survival following sepsis challenge.
Highlights
The endothelial monolayer lining the inner wall of blood vessels controls the transvascular flux of fluid, proteins, and cells across the vessel wall into underlying tissue [1,2,3]
Intractable endothelial injury characterized by persistently increased lung microvascular permeability resulting in protein-rich lung edema is a hallmark of acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) [4,5,6]
Employing the mouse model with endothelial cells (EC)-restricted disruption of FoxM1 (FoxM1 CKO), we have shown the critical role of FoxM1 in regulating endothelial proliferation and endothelial repair following lung vascular injury induced by LPS challenge [18]
Summary
The endothelial monolayer lining the inner wall of blood vessels controls the transvascular flux of fluid, proteins, and cells across the vessel wall into underlying tissue [1,2,3]. FoxM1 is expressed in proliferating cells including cancer cells, where it controls cell cycle progression into DNA replication (G1/S) and mitosis (G2/M), and silenced in terminally differentiated cells [12,13,14,15]. FoxM1 is essential for transcription expression of the S-phase kinaseassociated protein 2 and Cdk subunit 1 to regulate the degradation of Cdk inhibitor proteins p21Cip and p27Kip during the G1/S transition [13]. FoxM1 controls the transcription of genes critical for G2/M and mitotic progression including cyclin B1, Cdc25B and Cdc25C phosphatases, polo-like kinase 1 and aurora kniase [13,14]. FoxM1 transcriptional activity requires phosphorylation at Thr596 by either the S-phase or M-phase Cdk-cyclin complexes and subsequent recruitment of p300/CBP coactivator proteins [16]
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