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Angiogenesis

, Volume 22, Issue 4, pp 521–533 | Cite as

VEGFR2 activation mediates the pro-angiogenic activity of BMP4

  • Sara Rezzola
  • Margherita Di Somma
  • Michela Corsini
  • Daria Leali
  • Cosetta Ravelli
  • Viviane A. B. Polli
  • Elisabetta Grillo
  • Marco Presta
  • Stefania MitolaEmail author
Original Paper

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.

Keywords

Angiogenesis BMP4 VEGFR2 c-Src 

Notes

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.

Supplementary material

Supplementary material 1 (WMV 6345 kb)

10456_2019_9676_MOESM2_ESM.avi (34.1 mb)
Supplementary material 2 (AVI 34942 kb)
10456_2019_9676_MOESM3_ESM.pdf (299 kb)
Supplementary material 3 (PDF 298 kb)
10456_2019_9676_MOESM4_ESM.pdf (493 kb)
Supplementary material 4 (PDF 493 kb)

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Azienda Socio-sanitaria Territoriale Spedali Civili di BresciaBresciaItaly
  3. 3.Laboratory for Preventive and Personalized Medicine (MPP Lab)University of BresciaBresciaItaly
  4. 4.Department of Cellular Biology, Embryology and GeneticsFederal University of Santa CatarinaFlorianópolisBrazil

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