Research ArticleVASCULAR BIOLOGY

FOXF1 maintains endothelial barrier function and prevents edema after lung injury

Sci. Signal.  19 Apr 2016:
Vol. 9, Issue 424, pp. ra40
DOI: 10.1126/scisignal.aad1899

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Improving endothelial barrier in the lung

Acute lung injury decreases the ability of the endothelial cells lining pulmonary blood vessels to be an effective barrier, resulting in the accumulation of fluid in the lungs (a condition called pulmonary edema) and inflammation. Cai et al. found that, in adult lung endothelial cells, the transcription factor FOXF1 transcriptionally activated a gene encoding the receptor for S1P, a lipid mediator that enhances the barrier function of endothelial cells. Adult mice that lacked one Foxf1 allele in lung endothelial cells were more likely to develop pulmonary edema and die after acute lung injury, outcomes that were reversed by administration of S1P. Thus, therapies that increase the activity of FOXF1 or S1P signaling could be used to decrease the complications that arise after acute lung injury, which can require hospitalization and can be fatal.

Abstract

Multiple signaling pathways, structural proteins, and transcription factors are involved in the regulation of endothelial barrier function. The forkhead protein FOXF1 is a key transcriptional regulator of embryonic lung development, and we used a conditional knockout approach to examine the role of FOXF1 in adult lung homeostasis, injury, and repair. Tamoxifen-regulated deletion of both Foxf1 alleles in endothelial cells of adult mice (Pdgfb-iCreER/Foxf1−/−) caused lung inflammation and edema, leading to respiratory insufficiency and death. Deletion of a single Foxf1 allele made heterozygous Pdgfb-iCreER/Foxf1+/− mice more susceptible to acute lung injury. FOXF1 abundance was decreased in pulmonary endothelial cells of human patients with acute lung injury. Gene expression analysis of pulmonary endothelial cells with homozygous FOXF1 deletion indicated reduced expression of genes critical for maintenance and regulation of adherens junctions. FOXF1 knockdown in vitro and in vivo disrupted adherens junctions, enhanced lung endothelial permeability, and increased the abundance of the mRNA and protein for sphingosine 1-phosphate receptor 1 (S1PR1), a key regulator of endothelial barrier function. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that FOXF1 directly bound to and induced the transcriptional activity of the S1pr1 promoter. Pharmacological administration of S1P to injured Pdgfb-iCreER/Foxf1+/− mice restored endothelial barrier function, decreased lung edema, and improved survival. Thus, FOXF1 promotes normal lung homeostasis and repair, in part, by enhancing endothelial barrier function through activation of the S1P/S1PR1 signaling pathway.

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