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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1803.)
© 2004 American Heart Association, Inc.

Vascular Biology

Expression of Angiopoietin-2 in Endothelial Cells Is Controlled by Positive and Negative Regulatory Promoter Elements

Anja Hegen; Stefanie Koidl; Karin Weindel; Dieter Marmé; Hellmut G. Augustin; Ulrike Fiedler

From the Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, D-79106 Freiburg, Germany.

Correspondence to Dr Hellmut G. Augustin, Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Breisacher Str. 117, 79106 Freiburg, Germany. E-mail augustin{at}angiogenese.de

Objective— Angiopoietin-2 (Ang-2) is a non-signal transducing ligand of the endothelial receptor tyrosine kinase Tie-2. Ang-2 is produced by endothelial cells and acts as an autocrine regulator mediating vascular destabilization by inhibiting Angiopoietin-1-mediated Tie-2 activation. To examine the transcriptional regulation of Ang-2, we studied the Ang-2 promoter in endothelial cells and nonendothelial cells.

Methods and Results— The human Ang-2 promoter contains a 585-bp region around the transcriptional start site (–109 to +476) that is sufficient to control endothelial cell-specific and cytokine-dependent Ang-2 expression. Strong repressor elements of Ang-2-promoter activity are located in the 5'-region of the promoter and in the first intron. The Ets family transcription factors Ets-1 and Elf-1 act as strong enhancers of endothelial cell Ang-2-promoter activity. Ets-binding sites –4 and –7 act as positive regulators, whereas Ets-binding site –3 acts as negative regulator. Demethylation experiments revealed that the Ang-2 gene (in contrast to the Tie-2 gene) is not controlled by imprinting.

Conclusions— The data determine unique positive and negative regulatory mechanisms of endothelial cell Ang-2 expression and provide further evidence for the critical role of Ang-2 as a key autocrine regulator of vascular stability and responsiveness.

This study shows that (1) the Ang-2 promoter becomes specifically activated in endothelial cells, (2) Ang-2 promoter activity is regulated by VEGF and FGF-2, (3) negative regulatory elements control low basal Ang-2 promoter activity, and (4) Ets-1 and Elf-1 act as regulators of endothelial cell specific Ang-2 expression.

Key Words: angiogenesis • Ang-2 • Ets-1 • Elf-1 • endothelial cell

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