Endothelial cell–restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury
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
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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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 3

Time course of FoxM1 expression following LPS-induced lung microvascular injury.

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Time course of FoxM1 expression following LPS-induced lung microvascular...
(A) Quantitative analysis of FoxM1 mRNA levels in mouse lungs by QRT-PCR. Total RNA was extracted from lungs collected from either WT or FoxM1 CKO mice after LPS exposure (5 mg/kg BW) at indicated times. FoxM1 mRNA levels were normalized to cyclophilin. Data are expressed as mean ± SD, n = 3–4. *P < 0.05 WT versus CKO; **P < 0.05 versus basal WT. (B) FoxM1 mRNA expression in endothelial cell–enriched primary cultures isolated from WT mouse lungs. Total RNA was extracted from endothelial cell–enriched primary cultures (passage 2) treated with either PBS (basal), 1,000 U/ml of recombinant mouse TNF-α, or 10 μM of H2O2 for 22 hours. Data are expressed as mean ± SD, n = 3. *P < 0.05.