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VEGFR2 activation mediates the pro-angiogenic activity of BMP4

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Abstract

The Bone Morphogenetic Protein 4 (BMP4) regulates multiple biological processes, including vascular development and angiogenesis. Here, we investigated the role of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in mediating the angiogenic activity of BMP4. BMP4 induces a rapid relocation and phosphorylation of VEGFR2 on the endothelial cell membrane. These effects occur in the absence of a direct interaction of BMP4 and/or BMP receptors with VEGFR2. At variance, BMP4, by interacting with the BMPRI-II hetero-complex, induces c-Src phosphorylation which, in turn, activates VEGFR2, leading to an angiogenic response. Accordingly, the BMPR inhibitor dorsomorphin prevents c-Src activation and specific inhibition of c-Src significantly reduces downstream VEGFR2 phosphorylation and the angiogenic activity exerted by BMP4 in a chick embryo chorioallantoic membrane assay. Together, our data indicate that the pro-angiogenic activity exerted by BMP4 in endothelial cells is mediated by a BMPR-mediated intracellular transactivation of VEGFR2 via c-Src.

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (IG AIRC grant n° IG 17276 and AIRC grant n° IG 14395) to S.M and M.P.; S.R., M.DS. and E.G. were supported by AIRC fellowships; MPP Lab was supported by Fondazione Cariplo and Regione Lombardia.

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Authors and Affiliations

  1. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Sara Rezzola, Margherita Di Somma, Michela Corsini, Cosetta Ravelli, Elisabetta Grillo, Marco Presta & Stefania Mitola

  2. Azienda Socio-sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy

    Daria Leali

  3. Laboratory for Preventive and Personalized Medicine (MPP Lab), University of Brescia, Brescia, Italy

    Cosetta Ravelli & Stefania Mitola

  4. Department of Cellular Biology, Embryology and Genetics, Federal University of Santa Catarina, Florianópolis, Brazil

    Viviane A. B. Polli

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  1. Sara Rezzola
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Rezzola, S., Di Somma, M., Corsini, M. et al. VEGFR2 activation mediates the pro-angiogenic activity of BMP4. Angiogenesis 22, 521–533 (2019). https://doi.org/10.1007/s10456-019-09676-y

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