The vascular endothelium comprises a dynamic interface with the blood and acts as an integrator and transducer of both biomechanical (e.g. laminar shear stress) and biochemical stimuli (e.g. inflammatory cytokines). Exposure to laminar flow induces critical regulators of endothelial function, which confer potent anti-thrombotic, anti-adhesive, and anti-inflammatory properties. In contrast, exposure to inflammatory cytokines activates endothelial cells as evidenced by expression of adhesion molecules, which allows for the recruitment of leukocytes to the blood vessel wall. Genomic transcriptional profiling studies identified KLF2 as being induced by laminar flow and inhibited by the inflammatory cytokines. Overexpression of lung kruppel like factor (KLF2) potently inhibits inflammatory cytokine mediated induction of VCAM-1 and immune cell adhesion under dynamic flow. Furthermore, studies to date suggest that this occurs through inhibition of NF-kappaB a central regulator of inflammation. The studies in this proposal will (1) determine the molecular basis for KLF2's ability to inhibit VCAM-1 expression in response to inflammatory cytokines and (2) assess the role of KLF2 in vascular inflammation in vivo.
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