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GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2

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Abstract

GATA-binding protein 2 (GATA2) and LIM domain only 2 (Lmo2) form common transcription complexes during hematopoietic differentiation. Here we show that these two transcription factors also play a key role in endothelial cells (EC) and lymphatic EC (LEC) function. Primary EC and tumor-associated blood vessels expressed GATA2 and Lmo2. VEGF-induced sprouting angiogenesis in both differentiating embryonic stem cells (embryoid bodies) and primary EC increased GATA2 and Lmo2 levels. Conversely, silencing of GATA2 and Lmo2 expression in primary EC inhibited VEGF-induced angiogenic activity, including EC migration and sprouting in vitro, two key steps of angiogenesis in vivo. This inhibition of EC function was associated with downregulated expression of neuropilin-2 (NRP2), a co-receptor of VEGFRs for VEGF, at the protein, mRNA and promoter levels. NRP2 overexpression partially rescued the impaired angiogenic sprouting in the GATA2/Lmo2 knockdown EC, confirming that GATA2 and Lmo2 mediated EC function, at least in part, by directly regulating NRP2 gene expression. Furthermore, it was found that primary LEC expressed GATA2 and Lmo2 as well. Silencing of GATA2 and Lmo2 expression in LEC inhibited VEGF-induced LEC sprouting, also in a NRP2-dependent manner. In conclusion, our results demonstrate that GATA2 and Lmo2 cooperatively regulate VEGF-induced angiogenesis and lymphangiogenesis via NRP2.

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Acknowledgments

We thank Dr. Lena Claesson-Welsh (Department of Immunology, Genetics and Pathology, Uppsala University) for critical reading of the manuscript, and Melissa Anderson and Kristin Johnson for preparation of the manuscript and for artwork. Research reported in this publication was supported by the National Institutes of Health under award numbers CA37392 and CA45548 (M.K.). This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Laurens A. van Meeteren

    Present address: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

Authors and Affiliations

  1. Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Karp Building, Room 12.210, 1 Blackfan Circle, Boston, MA, 02115, USA

    Silvia Coma, Marc Allard-Ratick, Tomoshige Akino, Akiko Mammoto & Michael Klagsbrun

  2. Department of Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, MA, 02115, USA

    Silvia Coma, Marc Allard-Ratick, Tomoshige Akino & Michael Klagsbrun

  3. Department of Pathology, Children’s Hospital Boston, Harvard Medical School,, Boston, MA, 02115, USA

    Michael Klagsbrun

  4. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Laurens A. van Meeteren

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Coma, S., Allard-Ratick, M., Akino, T. et al. GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. Angiogenesis 16, 939–952 (2013). https://doi.org/10.1007/s10456-013-9370-9

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