Research article summary (published 8 Jun 2004):

Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1.

Full Abstract

Endothelial PAS domain protein 1 (EPAS1) is a basic-helix-loop-helix/PAS domain transcription factor that is expressed preferentially in vascular endothelial cells. EPAS1 shares high homology with hypoxia-inducible factor-1alpha (HIF-1alpha) and is reported to transactivate vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), and Tie2 promoters. In this study, we analyzed the role of EPAS1 in the process of angiogenesis. Using microarray technology, we looked for target genes regulated by EPAS1 in vascular endothelial cells. A total of 130 genes were upregulated by EPAS1, including fms-like tyrosine kinase-1 (Flt-1). Reporter analysis using human Flt-1 promoter and gel mobility shift assays showed that the heterodimer of EPAS1 and aryl hydrocarbon receptor nuclear translocator binds directly to HIF-1-binding site upstream of Flt-1 promoter and transactivates it. Small interfering RNA targeted to EPAS1 but not HIF-1alpha attenuated desferrioxamine-induced Flt-1 mRNA expression, thus EPAS1 is thought to play an essential role in hypoxic induction of Flt-1 gene. Furthermore, using mouse wound healing models, we demonstrated that adenovirus-mediated delivery of EPAS1 gene significantly induced the expression of VEGF, Flt-1, Flk-1, and Tie2 mRNA at the wound site and promoted mature angiogenesis. The proportion of the number of mural cells in newly formed vessels was significantly higher in EPAS1-treated wound area than VEGF-treated area. In conclusion, EPAS1 promotes Flt-1 gene expression and induces mRNA expression of VEGF, Flk-1, and Tie2, leading to enhancement of mature angiogenesis in vivo. Thus, EPAS1 may contribute to the construction of mature vessels by modulating the coordinated expressions of VEGF, Flt-1, Flk-1, and Tie2.

Author information

Author/s: Takeda, Norihiko (N); Maemura, Koji (K); Imai, Yasushi (Y); Harada, Tomohiro (T); Kawanami, Daiji (D); Nojiri, Takefumi (T); Manabe, Ichiro (I); Nagai, Ryozo (R);

Affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Circulation research (Circ Res), published in United States. (Language: eng)

Reference: 2004-Jul; vol 95 (issue 2) : pp 146-53

Dates: Created 2004/07/23; Completed 2005/02/08; Revised 2008/11/21;

PMID: 15192019, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Aryl Hydrocarbon Receptor Nuclear Translocator Basic Helix-Loop-Helix Transcription Factors Binding Sites Cattle Cells, Cultured - drug effects; metabolism Chemotaxis - drug effects DNA-Binding Proteins - metabolism; physiology Deferoxamine - pharmacology Dimerization Endothelial Cells - drug effects; metabolism Endothelium, Vascular - metabolism Extracellular Matrix Proteins - biosynthesis; genetics Gene Expression Profiling Gene Expression Regulation - drug effects; physiology Gene Therapy Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit

Hypoxia-Inducible Factor 1, alpha Subunit Male Mice Mice, Inbred BALB C Neovascularization, Physiologic - genetics Nuclear Proteins - physiology Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic RNA, Messenger - biosynthesis RNA, Small Interfering - pharmacology Receptor, TIE-2 - biosynthesis; genetics Receptors, Aryl Hydrocarbon - metabolism Recombinant Fusion Proteins - physiology Transcription Factors - genetics; metabolism; physiology Transcriptional Activation Vascular Endothelial Growth Factor A - biosynthesis; genetics; pharmacology Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 - biosynthesis; genetics Wound Healing - genetics

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: ARNT protein, human (0) ; Arnt protein, mouse (0) ; Basic Helix-Loop-Helix Transcription Factors (0) ; DNA-Binding Proteins (0) ; Extracellular Matrix Proteins (0) ; Fltn protein, mouse (0) ; HIF1A protein, human (0) ; Hif1a protein, mouse (0) ; Hypoxia-Inducible Factor 1 (0) ; Hypoxia-Inducible Factor 1, alpha Subunit (0) ; Nuclear Proteins (0) ; RNA, Messenger (0) ; RNA, Small Interfering (0) ; Receptors, Aryl Hydrocarbon (0) ; Recombinant Fusion Proteins (0) ; Transcription Factors (0) ; Vascular Endothelial Growth Factor A (0) ; endothelial PAS domain-containing protein 1 (0) ; Aryl Hydrocarbon Receptor Nuclear Translocator (138391-32-9) ; Deferoxamine (70-51-9) ; Flt1 protein, mouse (EC 2.7.1.112) ; Receptor, TIE-2 (EC 2.7.1.112) ; Vascular Endothelial Growth Factor Receptor-1 (EC 2.7.1.112) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.1.112) ; FLT1 protein, human (EC 2.7.10.1)

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