The vascular endothelium is a critical regulator of vascular function. Accumulating clinical and experimental studies strongly support the hypothesis that atherosclerosis is a chronic inflammatory disease state. Exposure to inflammatory cytokines results in the expression and/or elaboration of factors, which allow for immune cell recruitment and adhesion to the blood vessel wall. However, despite this systemic inflammatory state, the lesions of atherosclerosis show a non-random pattern of distribution such as branch points and areas of major curvature. These observations have led to the hypothesis that local events such as fluid mechanical forces can affect endothelial function. Indeed, experimental studies demonstrate that uniform laminar flow confers anti-proliferative, anti-thrombotic, anti-adhesive, and anti-oxidant properties to the endothelium. To obtain a greater understanding of how inflammatory stimuli and fluid forces impact on endothelial cell biology, we undertook a genomic profiling approach to assess global patterns of gene expression. These studies identified the transcription factor KLF2 as being induced by laminar shear stress and inhibited by the inflammatory cytokine IL-lbeta. Over expression of KLF2 in endothelial cells robustly induced the expression and activity of endothelial nitric oxide synthase - a central regulator of vascular homeostasis. In addition, KLF2 potently inhibits the induction of endothelial adhesion molecules such as VCAM-1 and E-selectin in response to diverse inflammatory stimuli. Consistent with these observations, in vitro flow assays demonstrate that immune cell attachment and rolling to an endothelial monolayer is markedly attenuated. Finally, our studies implicate recruitment of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these distinct effects of KLF2. These observations support an important role for KLF2 as a """"""""molecular switch"""""""" which regulates endothelial function.
In AIM 1 and 2 of this proposal studies will be undertaken to understand the molecular basis for KLF2 ability to both induce eNOS and inhibit the cytokine- mediated induction of adhesion molecules.
In AIM 3 we will overexpress, in an endothelial specific manner, KLF2 in vivo and assess for effects on vascular inflammation and vasoreactivity. These studies will provide a detailed understanding of KLF2 role in endothelial cell biology in health and disease states.
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