Abstract 17222: Kruppel Like Factor-4 (KLF4) Regulates Vascular Endothelial Barrier Function
The transmembrane Vascular Endothelial (VE)-cadherin and Claudin-5 proteins are localized in Adherens Junctions (AJ) and Tight Junctions (TJs) of vascular endothelial cells (ECs), respectively. Both VE-cadherin and Claudin-5 are known to regulate endothelial barrier function, leukocyte trafficking, and angiogenesis, however, the underlying transcriptional mechanisms regulating these processes are less known. The goal of this study was to examine the relationship of transcription factor Kruppel Like Factor-4 (KLF4) in the mechanisms of VE-cadherin and Claudin-5 expression and their barrier protective functions. We observed that both VE-cadherin and Claudin-5 promoter region contain several potential KLF4 binding sites. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assays indicated binding of KLF4 with the VE-cadherin promoter DNA sequences. Accordingly, Klf4-depletion decreased VE-cadherin and Claudin-5 levels, and transendothelial electrical resistance (TEER) in vitro, and increased lung microvascular endothelial permeability in vivo. Together, these data strongly implicate Klf4 as a key regulator of VE-cadherin and Claudin-5 expression in ECs. Our data also suggest that VE-cadherin and Claudin-5 expressions resulting from the activation of KLF4 can potentially aid in the normalization of endothelial barrier integrity, play atheroprotective role, and prevent vascular leakage. *Studies were supported by National Institutes of Health grants (R01HL079356; HL079356-03S1) and by the University of Illinois, Chicago (UIC) Center for Clinical and Translational Science (CCTS) Award Number UL1RR029879 from the National Center for Research Resources to K.K.W. C.E.C. was supported by T32HL072742 and E.E.K. by T32GM070388 NIH training grants.
- © 2010 by American Heart Association, Inc.