FoxM1 Is Essential for Endothelial Repair following Inflammatory Injury

Abstract

The Forkhead transcription factor FoxM1 regulates expression of cell cycle genes critical for cellular proliferation. Here, we observed that FoxM1 expression was predominantly induced in endothelial cells in the recovery phase following lipopolysacchride-induced vascular injury. To further investigate the functional role of FoxM1 in the mechanism of endothelial repair, we generated endothelial cell-restricted FoxM1-deficient mice (FoxM1 CKO). Unlike the FoxM1 null mutation mice, these conditional mutant mice are viable and exhibited no overt phenotype. However, in response to the inflammatory mediator lipopolysaccharide, FoxM1 CKO displayed a significantly protracted increase in lung vascular permeability and a marked increase in mortality. BrdU labeling studies demonstrated significantly impaired cellular proliferation in FoxM1 CKO lungs following LPS challenge, which was associated with a persistent increase in expression of the cyclin-dependent kinase inhibitor p27kip1. In addition, endothelial cells isolated from FoxM1 CKO lungs failed to proliferate and siRNA-mediated suppression of FoxM1 expression in human endothelial cells resulted in defective cell cycle progression. Taken together, these data suggest FoxM1 plays a critical role in the mechanism of the restoration of endothelial barrier integrity following vascular injury.