The vascular endothelium comprises a dynamic interface with the blood and acts as an integrator and transducer of both biochemical (e.g. inflammatory cytokines) and biomechanical (e.g. laminar shear stress) stimuli. Stimulation of the endothelium with pro-inflammatory cytokines renders the endothelium dysfunctional and induces a proadhesive and pro-thrombotic phenotype. In contrast, exposure to laminar flow induces critical gene products that confer potent anti-thrombotic, anti-adhesive, and anti-inflammatory properties. The balance of these biochemical and biomechanical stimuli critically regulates vascular function under physiologic and pathologic condition. KLF4 is a member of the Kruppel-like family of zinc-finger transcription factors that regulate critical processes such as cellular differentiation and function. Studies in our laboratory demonstrate that KLF4 is expressed in arterial and venous endothelial cells (ECs) in vitro and in vivo. Exposure of endothelial cells to pro-inflammatory stimuli or laminar shear stress induces KLF4 expression. In vitro gain and loss-of-function studies reveal that (1) KLF4 inhibits the cytokine-induced expression of pro-adhesive, prothrombotic factors such VCAM-1 and tissue factor (TF) and (2) KLF4 induces the expression of flow-regulated factors such as endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM). Consistent with these differential effects on target genes, sustained expression of KLF4 inhibits immune cell adhesion to an endothelial monolayer and prolongs blood-clotting time. Based on these observations, we hypothesize that KLF4 may serve as a critical transcriptional regulator of endothelial cell function and vascular homeostasis. The studies outlined in this proposal will explore (1) the molecular basis and functional consequences of altering KLF4 expression on cytokine-mediated EC activation in vitro, (2) the molecular basis for flow-mediated induction of KLF4 and the functional consequences of altering KLF4 levels on endothelial gene expression in vitro, and (3) the effect of KLF4 over expression and deficiency on endothelial gene expression and vessel function in vivo. The results of the studies outlined in this proposal will provide insights regarding KLF4 function in EC biology under physiologic and pathologic states. In addition, they may provide the foundation for novel therapies directed at a broad spectrum of vascular inflammatory disease states such atherosclerosis.
The vascular endothelium comprises a dynamic interface with the blood and acts as an integrator and transducer of both biochemical (e.g. inflammatory cytokines) and biomechanical (e.g. laminar shear stress) stimuli. The molecular mechanisms regulating the effect of these diverse stimuli on vessel biology remain poorly understood. This application explores the role of a factor termed KLF4 in endothelial homeostasis.
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