Klf2 Provokes a Gene Expression Pattern That Establishes Functional Quiescent Differentiation of the Endothelium.
From: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Blood
- Publish Date: Jun 2006
- ISSN: 0006-4971
- Volume: 107
- Issue: 11
- Pages: 4354-63
- Medium: Print
- Language: English
- Citation (JAMA): Dekker Rob J, Boon Reinier A, Rondaij Mariska G, et al. Klf2 Provokes a Gene Expression Pattern That Establishes Functional Quiescent Differentiation of the Endothelium.. Blood Jun 2006;107:4354-63
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-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.
Mesh Headings (Keywords): Cell Differentiation, Cell Movement, Cell Shape, Cells, Cultured, Endothelium, Vascular, Gene Expression Profiling, Gene Expression Regulation, Genome, Human, Humans, Kruppel-Like Transcription Factors, Umbilical Veins, von Willebrand Factor
Check for Full Text / PubMed Unique Identifier (PMID): 16455954
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