The vascular endothelium is a critical integrator and transducer of various physiologic and pathologic stimuli. Indiabetes, the enhanced production of pro-inflammatory cytokines, advanced glycation endproducts, andactivation of specific signaling pathways (e.g. protein kinase C, PKC) alter endothelial function. Characteristicabnormalities include reduced endothelium dependent vasodilation, enhanced expression of leukocyteadhesion molecules, and increased elaboration of procoagulant factors. As a consequence of these effects,diabetic patients exhibit an accelerated and aggressive form of micro- and macro-vascular arteriopathy.KLF2 is a member of the Kruppel-like family of zinc-finger transcription factors that is expressed in vascularendothelial cells and induced by laminar flow. KLF2 overexpression in endothelial cells potently inducesendothelial nitric oxide synthase (eNOS) expression and activity. In addition, KLF2 inhibits the inflammatorycytokine and PKC mediated induction of adhesion molecules (e.g. VCAM-1, E-selectin) and procoagulantfactors (e.g. PAI-1, tissue factor). Conversely, KLF2 expression in endothelial cells is strongly inhibited byhyperglycemia, advanced glycation products, activation of PKC pathway, and pro-inflammatory cytokines. Onthe basis of these observations we hypothesize that (1) KLF2 is a key regulator of endothelial cell functionunder physiologic states and (2) reduction in KLF2 expression by pathologic stimuli is a critical event in thedevelopment of diabetic vascular disease. The studies below will examine the molecular mechanismsregulating KLF2 expression in endothelial cells and the functional consequences of altering KLF2 levels onendothelial function in vitro and in vivo. These studies will provide insight into the role of this factor inendothelial cell biology and may serve as the foundation for novel strategies to modulate endothelial cellfunction under physiologic and pathologic states.
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