Krüppel-Like Factor-4 Transcriptionally Regulates VE-Cadherin Expression and Endothelial Barrier Function

• Published in: Circulation research 2010-10, Vol.107 (8), p.959-966
• Main Authors: Cowan, Colleen E, Kohler, Erin E, Dugan, Tracey A, Mirza, M Kamran, Malik, Asrar B, Wary, Kishore K
• Format: Article
• Language: English
• Subjects: Adherens Junctions - physiology; Animals; Antigens, CD - genetics; Biological and medical sciences; Cadherins - genetics; Capillary Permeability - physiology; Cells, Cultured; Endothelial Cells - immunology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - immunology; Humans; Kruppel-Like Transcription Factors - physiology; Lipopolysaccharides - pharmacology; Mice; Mice, Knockout; Neutrophils - cytology; Neutrophils - immunology; Pneumonia - immunology; Pneumonia - metabolism; Pneumonia - physiopathology; Promoter Regions, Genetic - physiology; Signal Transduction - immunology; Umbilical Veins - cytology; Vertebrates: cardiovascular system; Wnt Proteins - metabolism; Wnt Proteins - pharmacology; Wnt3 Protein
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.219592

RATIONALE: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. METHODS AND 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. CONCLUSION: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.