FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of beta-catenin expression.
Repair of the injured vascular intima requires a series of coordinated events that mediate both endothelial regeneration and reannealing of adherens junctions (AJs) to form a restrictive endothelial barrier. The forkhead transcription factor FoxM1 is essential for endothelial proliferation after vascular injury. However, little is known about mechanisms by which FoxM1 regulates endothelial barrier reannealing. Here, using a mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO) and primary cultures of ECs with small interfering RNA (siRNA)-mediated knockdown of FoxM1, we demonstrate a novel requisite role of FoxM1 in mediating endothelial AJ barrier repair through the transcriptional control of beta-catenin. In the FoxM1 CKO lung vasculature, we observed persistent microvessel leakage characterized by impaired reannealing of endothelial AJs after endothelial injury. We also showed that FoxM1 directly regulated beta-catenin transcription and that reexpression of beta-catenin rescued the defective AJ barrier-reannealing phenotype of FoxM1-deficient ECs. Knockdown of beta-catenin mimicked the phenotype of defective barrier recovery seen in FoxM1-deficient ECs. These data demonstrate that FoxM1 is required for reannealing of endothelial AJs in order to form a restrictive endothelial barrier through transcriptional control of beta-catenin expression. Therefore, means of activating FoxM1-mediated endothelial repair represent a new therapeutic strategy for the treatment of inflammatory vascular diseases associated with persistent vascular barrier leakiness such as acute lung injury.
Mirza
Muhammad K
MK
Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Sun
Ying
Y
Zhao
Yidan D
YD
Potula
Hari-Hara S K
HH
Frey
Randall S
RS
Vogel
Steven M
SM
Malik
Asrar B
AB
Zhao
You-Yang
YY
D022005:Adherens Junctions / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D051177:Catenins / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D051185:gamma Catenin / Q000235:genetics; D000095002:Delta Catenin
C495270:CTNNB1 protein, human; D051177:Catenins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C495293:Jup protein, mouse; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D034741:RNA, Small Interfering; D051176:beta Catenin; D051185:gamma Catenin; D013917:Thrombin; D000095002:Delta Catenin