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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

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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 6

Failure of WT bone marrow cells to rescue the vascular repair defect in FoxM1 CKO mice following LPS challenge.

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Failure of WT bone marrow cells to rescue the vascular repair defect in ...
(A) FACS analysis of GFP-positive bone marrow lymphocytes (lymph) and total white blood cells. At 3 weeks following transplantation of WT bone marrow cells isolated from GFP-transgenic mice, bone marrow cells were isolated from reconstituted FoxM1 CKO and red blood cells were lysed prior to FACS analysis. Bone marrow white blood cells isolated from C57B6 mice and GFP-transgenic mice were used as negative and positive controls, respectively. Approximately 80% of bone marrow reconstitution was achieved. BMT, WT bone marrow cell–transplanted FoxM1 CKO. (B) Sustained increase in lung microvessel permeability in WT bone marrow cell–transplanted FoxM1 CKO following LPS challenge. At 5 weeks following WT bone marrow transplantation, lungs from WT or FoxM1 CKO mice were isolated for Kf,c measurement. Data are expressed as mean ± SD, n = 3–5 per group. *P < 0.001 versus basal; **P < 0.001, CKO versus WT. Basal, 0.2 ml PBS. CKO, FoxM1 CKO mice reconstituted with WT bone marrow cells. (C) Quantitative analysis of FoxM1 mRNA expression in bone marrow cells. Bone marrow white blood cells were isolated from either WT or FoxM1 CKO at the indicated time points following LPS challenge, and RNA was isolated for QRT-PCR analysis. FoxM1 mRNA levels were normalized to cyclophilin. Data are expressed as mean ± SD, n = 3 per group. In contrast to endothelial cells isolated from FoxM1 CKO lungs, the white blood cells from FoxM1 CKO bone marrow expressed FoxM1 at the same level as WT.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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