Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2)

作者：Rob J. Dekker, S. van Soest, Ruud D. Fontijn, S. Salamanca, Philip G. de Groot, Ed VanBavel, Hans Pannekoek, Anton J.G. Horrevoets · 发表于：Blood · 年份：2002 · DOI：10.1182/blood-2002-01-0046 · 被引用次数：695 · 研究领域：Kruppel-like factors research、TGF-β signaling in diseases、Angiogenesis and VEGF in Cancer

The endothelium expresses a large repertoire of genes under apparent transcriptional control of biomechanical forces, many of which are neither cell-type nor flow specific. We set out to identify genes that are uniquely flow responsive in human vascular endothelial cells. Transcriptional profiling using commercial DNA microarrays identified 12 of 18 000 genes that were modulated at least 5-fold after 24 hours of steady laminar flow (25 dyne/cm(2)). After a 7-day exposure to unidirectional pulsatile flow (19 +/- 12 dyne/cm(2)), only 3 of 12 remained elevated at least 5-fold. A custom microarray of ~300 vascular cell-related gene fragments was constructed, and expression analysis revealed that many flow-induced genes are also induced by at least one of the following agents: tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), transforming growth factor-beta, vascular endothelial growth factor, or thrombin, indicating a more general role in adaptive or stress responses. Most flow-induced genes were also induced by TNF-alpha but not IL-1beta, suggesting the involvement of reactive oxygen species. A limited panel of genes that are unique for flow-exposed cultures was identified, including lung Krüppel-like factor (LKLF/KLF2) and cytochrome P450 1B1 (CYP1B1). In marked contrast, both these genes were substantially repressed by TNF-alpha. LKLF but not CYP1B1 mRNA was detected exclusively in the vascular endothelium of healthy human aorta by in situ hybridization an...