KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium

Rob J. Dekker, Reinier A. Boon, Mariska G. Rondaij, Astrid Kragt, Oscar L. Volger, Yvonne W. Elderkamp, Joost C.M. Meijers, Jan Voorberg, Hans Pannekoek, Anton J.G. Horrevoets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The flow-responsive transcription factor KLF2 is acquiring a leading role in the regulation of endothelial cell gene expression. A genome-wide microarray expression profiling is described employing lentivirus-mediated, 7-day overexpression of human KLF2 at levels observed under prolonged flow. KLF2 is not involved in lineage typing, as 42 endothelial-specific markers were unaffected. Rather, KLF2 generates a gene transcription profile(> 1000 genes) affecting key functional pathways such as cell migration, vasomotor function, inflammation, and hemostasis and induces a morphology change typical for shear exposure including stress fiber formation. Protein levels for thrombomodulin, endothelial nitric oxide synthase, and plasminogen activator inhibitor type-1 are altered to atheroprotective levels, even in the presence of the inflammatory cytokine TNF-α. KLF2 attenuates cell migration by affecting multiple genes including VEGFR2 and the potent antimigratory SEMA3F. The distribution of Weibel-Palade bodies in cultured cell populations is normalized at the single-cell level without interfering with their regulated, RalA-dependent release. In contrast, thrombin-induced release of Weibel-Palade bodies is significantly attenuated, consistent with the proposed role of VWF release at low-shear stress regions of the vasculature in atherosclerosis. These results establish that KLF2 acts as a central transcriptional switch point between the quiescent and activated states of the adult endothelial cell.

Original languageEnglish
Pages (from-to)4354-4363
Number of pages10
JournalBlood
Volume107
Issue number11
DOIs
Publication statusPublished - 1 Jun 2006

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