Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury.
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 p27(Kip1) 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 p27(Kip1) 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.
Zhao
You-Yang
YY
Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA. yyzhao@uic.edu
Gao
Xiao-Pei
XP
Zhao
Yidan D
YD
Mirza
Muhammad K
MK
Frey
Randall S
RS
Kalinichenko
Vladimir V
VV
Wang
I-Ching
IC
Costa
Robert H
RH
Malik
Asrar B
AB
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D011652:Pulmonary Circulation; D034741:RNA, Small Interfering / Q000235:genetics
D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering