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

• Published in: Blood Vol. 107; no. 11; pp. 4354 - 4363
• Main Authors: Dekker, Rob J., Boon, Reinier A., Rondaij, Mariska G., Kragt, Astrid, Volger, Oscar L., Elderkamp, Yvonne W., Meijers, Joost C.M., Voorberg, Jan, Pannekoek, Hans, Horrevoets, Anton J.G.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.06.2006; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Cell Differentiation - genetics; Cell Movement; Cell Shape; Cells, Cultured; Endothelium, Vascular - cytology; Gene Expression Profiling - methods; Gene Expression Regulation; Genome, Human; Hematologic and hematopoietic diseases; Humans; Kruppel-Like Transcription Factors - physiology; Medical sciences; Umbilical Veins; von Willebrand Factor - analysis; von Willebrand Factor - genetics; Human; Endothelial cell; Regulation(control); Cell differentiation; Gene expression; Lung Kruppel like factor; Endothelium; Gene expression profile
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-08-3465

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.