Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function.
BACKGROUND
Vascular endothelial (VE)-cadherin localized at adherens junctions (AJs) regulates endothelial barrier function. Because WNT (wingless) signaling-induced activation of the transcription factor Krüppel-like factor (KLF)4 may have an important role in mediating the expression of VE-cadherin and AJ integrity, we studied the function of KLF4 in regulating VE-cadherin expression and the control of endothelial barrier function.


OBJECTIVE
The goal of this study was to determine the transcriptional role of KLF4 in regulating VE-cadherin expression and endothelial barrier function.


RESULTS
Expression analysis, microscopy, chromatin immunoprecipitation, electrophoretic mobility shift assays, and VE-cadherin-luciferase reporter experiments demonstrated that KLF4 interacted with specific domains of VE-cadherin promoter and regulated the expression of VE-cadherin at AJs. KLF4 knockdown disrupted the endothelial barrier, indicating that KLF4 is required for normal barrier function. In vivo studies in mice showed augmented lipopolysaccharide-induced lung injury and pulmonary edema following Klf4 depletion.


CONCLUSIONS
Our data show the key role of KLF4 in the regulation of VE-cadherin expression at the level of the AJs and in the acquisition of VE-cadherin-mediated endothelial barrier function. Thus, KLF4 maintains the integrity of AJs and prevents vascular leakage in response to inflammatory stimuli.
Cowan
Colleen E
CE
Department of Pharmacology, University of Illinois, 835 S Wolcott, Room E403, Mail code 868, Chicago, IL 60612, USA.
Kohler
Erin E
EE
Dugan
Tracey A
TA
Mirza
M Kamran
MK
Malik
Asrar B
AB
Wary
Kishore K
KK
D022005:Adherens Junctions / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002199:Capillary Permeability / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014471:Umbilical Veins / Q000166:cytology; D051153:Wnt Proteins / Q000378:metabolism / Q000494:pharmacology; D060508:Wnt3 Protein; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D051153:Wnt Proteins; D060508:Wnt3 Protein; D000099152:Cadherin 5; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse