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 7

Decreased cell proliferation in FoxM1 CKO lungs following LPS-induced lung microvascular injury.

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Decreased cell proliferation in FoxM1 CKO lungs follow...
(A) Representative micrographs of BrdU immunostaining. Cryosections of lungs (3- to 5-μm thick), collected 72 hours after LPS challenge, were stained with FITC-conjugated anti-BrdU antibody to identify proliferating cells; nuclei were counterstained with DAPI. Scale bar: 25 mm. (B) Graphic representation of decreased BrdU incorporation in FoxM1 CKO lungs and WT lungs at the indicated times following LPS challenge (5 mg/kg BW). From 3 to 4 consecutive cryosections from each mouse lung were examined, and the average number of BrdU-positive nuclei per 2,000 nuclei was used as the value for the mouse. Data are expressed as mean ± SD, n = 3–4 mice per time point. *P < 0.05 versus WT at 48 and 72 hours after LPS. There are few BrdU-positive nuclei (<1 BrdU positive nuclei per 2,000 nuclei) in both WT and FoxM1 CKO lungs in the absence of LPS challenge. (C) Graphic representation of decreased proliferating endothelial cells (double-positive staining of vWF and BrdU) in FoxM1 CKO lungs. Data are expressed as mean ± SD, percentage of total nuclei, n = 3–4 mice per time point per group. *P < 0.05 versus WT.