FOXF1 maintains endothelial barrier function and prevents edema after lung injury.
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.
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Yuqi
Y
Cai
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Craig
C
Bolte
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Tien
T
Le
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Chinmayee
C
Goda
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Yan
Y
Xu
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. The Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA. vladimir.kalinichenko@cchmc.org tatiana.kalin@cchmc.org.
Tanya V
TV
Kalin
Division of Pulmonary Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. The Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA. vladimir.kalinichenko@cchmc.org tatiana.kalin@cchmc.org.
Vladimir V
VV
Kalinichenko
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004487:Edema / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D008246:Lysophospholipids / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine