KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium.
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-alpha. 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.
Dekker
Rob J
RJ
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Boon
Reinier A
RA
Rondaij
Mariska G
MG
Kragt
Astrid
A
Volger
Oscar L
OL
Elderkamp
Yvonne W
YW
Meijers
Joost C M
JC
Voorberg
Jan
J
Pannekoek
Hans
H
Horrevoets
Anton J G
AJ
D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D014471:Umbilical Veins; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics
C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D014841:von Willebrand Factor