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 2

Impaired lung vascular endothelial barrier reannealing following LPS-induced microvascular injury in FoxM1 CKO mice.

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Impaired lung vascular endothelial barrier reannealing following LPS-ind...
(A) Time course of increase in lung microvessel permeability as measured by Kf,c. Basal, 0.2 ml PBS; LPS, 5 mg/kg BW. Data are expressed as mean ± SD, n = 3–5 per group. *P < 0.001 versus basal; **P < 0.001, CKO versus WT; #P < 0.05, CKO versus WT. (B) Representative graphs of mouse lung wet weights continuously recorded during measurement of microvessel permeability. 48h-LPS, 48 hours after LPS challenge. (C and D) Time course of loss of isogravimetric state of lungs (edema formation) obtained from mouse lungs at indicated times after LPS challenge. WT (C) and FoxM1 CKO mice (D) are represented. Points indicate mean ± 1 SD, n = 3–5 mice per group. #P < 0.05 WT or CKO 6 hours after LPS challenge (6h-LPS) versus basal; ##P < 0.05 CKO 48 hours after LPS challenge (48h-LPS) versus CKO basal or WT 48 hours after LPS challenge; ΧP < 0.05 CKO 96 hours after LPS challenge (96h-LPS) versus CKO basal or WT 96 hours after LPS challenge. (E) Representative micrographs of H&E staining show perivascular leukocyte infiltration in FoxM1 CKO lungs 96 hours after LPS challenge (5 mg/kg). Arrows indicate leukocyte infiltration. Br, bronchia; S, small vessels (<150 μm in diameter); L, large vessels (>150 μm in diameter). Scale bar: 50 mm. (F) Quantitative analysis of infiltrating leukocytes in lungs at 96 hours after LPS challenge. Bar graphs show infiltrating leukocytes in vessels of different diameters. Percentages of vessels of different diameters exhibiting leukocyte infiltration are shown. Data are expressed as mean ± SD, n = 3–4. #P < 0.05 versus WT (infiltrating leukocytes per vessel); ##P < 0.05 versus WT (% of vessels).