Endothelial Hypoxia-Inducible Factor-1α Is Required for Vascular Repair and Resolution of Inflammatory Lung Injury through Forkhead Box Protein M1

Abstract

Endothelial barrier dysfunction is a central factor in the pathogenesis of persistent lung inflammation and protein-rich edema formation, the hallmarks of acute respiratory distress syndrome. However, little is known about the molecular mechanisms that are responsible for vascular repair and resolution of inflammatory injury after sepsis challenge. Herein, we show that hypoxia-inducible factor-1α (HIF-1α), expressed in endothelial cells (ECs), is the critical transcriptional factor mediating vascular repair and resolution of inflammatory lung injury. After sepsis challenge, HIF-1α but not HIF-2α expression was rapidly induced in lung vascular ECs, and mice with EC-restricted disruption of Hif1α (Hif1a^f/f/Tie2Cre⁺) exhibited defective vascular repair, persistent inflammation, and increased mortality in contrast with the wild-type littermates after polymicrobial sepsis or endotoxemia challenge. Hif1a^f/f/Tie2Cre⁺ lungs exhibited marked decrease of EC proliferation during recovery after sepsis challenge, which was associated with inhibited expression of forkhead box protein M1 (Foxm1), a reparative transcription factor. Therapeutic restoration of endothelial Foxm1 expression, via liposomal delivery of Foxm1 plasmid DNA to Hif1a^f/f/Tie2Cre⁺ mice, resulted in reactivation of the vascular repair program and improved survival. Together, our studies, for the first time, delineate the essential role of endothelial HIF-1α in driving the vascular repair program. Thus, therapeutic activation of HIF-1α-dependent vascular repair may represent a novel and effective therapy to treat inflammatory vascular diseases, such as sepsis and acute respiratory distress syndrome.