Endothelial cell–restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury
You-Yang Zhao, … , Robert H. Costa, Asrar B. Malik
You-Yang Zhao, … , Robert H. Costa, Asrar B. Malik
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2333-2343. https://doi.org/10.1172/JCI27154.
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Research Article Vascular biology

Endothelial cell–restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury

Abstract

Recovery of endothelial integrity after vascular injury is vital for endothelial barrier function and vascular homeostasis. However, little is known about the molecular mechanisms of endothelial barrier repair following injury. To investigate the functional role of forkhead box M1 (FoxM1) in the mechanism of endothelial repair, we generated endothelial cell–restricted FoxM1-deficient mice (FoxM1 CKO mice). These mutant mice were viable and exhibited no overt phenotype. However, in response to the inflammatory mediator LPS, FoxM1 CKO mice displayed significantly protracted increase in lung vascular permeability and markedly increased mortality. Following LPS-induced vascular injury, FoxM1 CKO lungs demonstrated impaired cell proliferation in association with sustained expression of p27Kip1 and decreased expression of cyclin B1 and Cdc25C. 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. Deletion of FoxM1 in endothelial cells induced decreased expression of cyclins, Cdc2, and Cdc25C, increased p27Kip1 expression, and decreased Cdk activities. Thus, FoxM1 plays a critical role in the mechanism of the restoration of endothelial barrier function following vascular injury. These data suggest that impairment in FoxM1 activation may be an important determinant of the persistent vascular barrier leakiness and edema formation associated with inflammatory diseases.

Authors

You-Yang Zhao, Xiao-Pei Gao, Yidan D. Zhao, Muhammad K. Mirza, Randall S. Frey, Vladimir V. Kalinichenko, I-Ching Wang, Robert H. Costa, Asrar B. Malik

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Figure 4

FoxM1 CKO mice exhibit endothelial apoptosis and lung neutrophil sequestration similar to that of WT mice in the early period following LPS challenge.

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FoxM1 CKO mice exhibit endothelial apoptosis and lung neutrophil seques...
(A) Representative micrographs of TUNEL staining. Cryosections of lungs (3- to 5-μm thick) collected 24 hours after LPS challenge were stained with FITC-conjugated TUNEL to identify apoptotic cells and anti-vWF antibody to identify endothelial cells; nuclei were counterstained with DAPI. Arrows, TUNEL+vWF+ cells. Scale bar: 25 mm. (B) Graphic representation of apoptotic endothelial cells and nonendothelial cells in FoxM1 CKO and WT lungs 24 hours after LPS challenge (5 mg/kg BW). The number of TUNEL-positive nuclei and vWF-positive cells from 3 to 4 consecutive cryosections from each mouse lung were averaged. Data are expressed as mean ± SD, n = 3–4 mice per group. There is no difference between WT and FoxM1 CKO. (C) Lung tissue myeloperoxidase (MPO) activity during basal period and 6 hours after LPS challenge (5 mg/kg BW). Data are expressed as mean ± SD, n = 4 mice per group. *P > 0.1 versus WT. Although there is a significant increase in MPO activity in mouse lungs 6 hours following LPS challenge, both WT and FoxM1 CKO lungs exhibit similar MPO activities, indicating a similar extent of polymorphonuclear leukocyte sequestration.