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Constitutive expression of the DNA-binding domain of Ets1 increases endothelial cell adhesion and stimulates their organization into capillary-like structures

Oncogene volume 19, pages 762–772 (2000)Cite this article

Abstract

We previously reported that the Ets1 transcription factor is expressed in endothelial cells during angiogenesis both in normal and pathological development. We analyse here the effects of the stable expression of an Ets transdominant negative mutant (Ets1-DB), consisting in an Ets1 protein lacking its transactivation domain. A retrovirus containing the Ets1-DB sequence fused to an IRES-Neo sequence was designed and used to infect brain capillary (IBE) and aorta (MAE) mouse endothelial cell lines. Cells expressing this Ets1 mutant were examined for proliferation, migration and adhesion. Consistent changes were observed on cell morphology, with increased spreading and modifications in the organization of the cytoskeleton, and increased cell adhesion. We investigated the ability of endothelial cells to organise into capillary-like structures using three-dimensional gels. On Matrigel, all endothelial cell lines formed a cord-like network within 24 h, with an increased ability of Ets1-DB cells to spread on this substrate. In long term cultures, IBE cells expressing Ets1-DB showed a higher capacity to form branched structures; this effect was potentiated by FGF2. These results demonstrate a role of the Ets transcription factors in the regulation of the adhesive and morphogenetic properties of endothelial cells.

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Acknowledgements

We thank Dr P Robbins (Department of Molecular Genetics and Biochemistry, Pittsburg, USA) for the pCITE plasmid and Dr R Mulligan (Whitehead Institute, Cambridge, Massachusetts) for the MFG vector. We also thank Dr A Bank (Columbia University, New York) for the virus packaging murine fibroblasts GP+E86, Dr R Auerbach (University of Wisconsin, Madison) for the murine aortic endothelial cells, Dr L Claesson-Welsh (Ludwig Institute for Cancer Research, Uppsala) for the murine brain capillary endothelial cells and Dr J L Darlix (Ecole Normale Superieure, Lyon) for the murine fibroblasts (NIH3T3). We are grateful to Dr Y S Kanwar (Northwestern University, Chicago, USA) and Dr B Hierck (Leiden University, Leiden, The Netherlands) for providing the αV, α6 and β1 integrin probes respectively. We thank Gérard Torpier, Véronique Chevrier and Monique Arpin for their assistance with the immunofluorescence experiments, Agnès Bégue for cloning the MFG-Neo plasmid and Eric Maire for the use of Visilog software and the evaluation of the number of adhesion contacts. This work has been supported by the CNRS, the Institut Pasteur de Lille, and by grants from the Association pour la Recherche contre le Cancer, Fondation de France and the Association for International Cancer Research. V. Mattot was a recipient of a fellowship from the Ministère de la Recherche et de l'Enseignement Supérieur, from the Association pour la Recherche contre le Cancer and from the Fondation pour la Recherche Médicale. F Soncin and V Fafeur are chargés de recherches à l'INSERM.

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  1. Virginie Mattot

    Present address: Virginie Mattot, Center for Transgene Technology and Gene Therapy, Flanders InterUniversity Institute for Biotechnology, Campus Gasthuisberg, O&N, Leuven, B3000, Belgium

  2. Thierry Calmels

    Present address: Thierry Calmels, SmithKline Beecham, Laboratoires Pharmaceutiques, 4 rue du Chesnay Beauregard, BP 58, Saint Grégoire, 35762, France

  3. Christelle Huguet

    Present address: Discovery Biology Department, Christelle Huguet, Pfizer Limited, Sandwich, Kent, CT13 9NJ, UK

Authors and Affiliations

  1. CNRS EP560 – Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue Calmette, Lille, 59021, France

    Virginie Mattot, Chantal Vercamer, Fabrice Soncin, Thierry Calmels, Christelle Huguet, Véronique Fafeur & Bernard Vandenbunder

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Mattot, V., Vercamer, C., Soncin, F. et al. Constitutive expression of the DNA-binding domain of Ets1 increases endothelial cell adhesion and stimulates their organization into capillary-like structures. Oncogene 19, 762–772 (2000). https://doi.org/10.1038/sj.onc.1203248

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