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Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1

Nature Medicine volume 9, pages 936–943 (2003)Cite this article

Abstract

Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.

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Figure 1: Intermolecular transphosphorylation of Flk1 by PGF-activated Flt1.
Figure 2: Intermolecular transphosphorylation of Flk1 by PGF-activated Flt1.
Figure 3: Mass spectrometry and amplification of VEGF by PGF.
Figure 4: Intramolecular cross talk through Flk1/Flt1 heterodimerization.

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Acknowledgements

The authors thank G. Breier for VEGF receptor constructs; S. Suarez (Switzerland), P. Schaeffer (Synthélabo), N. Meyer (Ulm), M. Tucci (Geymonat), M. Röttgen (Basel), and K. Bijnens, A. Bouché, K. Clijsters, S. De Cat, K. De Roover, E. Gils, B. Hermans, S. Jansen, L. Kieckens, Y.W. Man, A. Manderveld, K. Maris, T. Vancoetsem, A. Vandenhoeck, A. Van den Boomen, P. Van Wesemael and S. Wyns (Leuven) for assistance; and B. Nürnberg for discussion. This work was supported in part by the European Union (Biomed BMH4-CT98-3380), Actie Levenslijn (#7.0019.98), European Union (Fifth Framework QLRT-2001-01955), Fonds voor Wetenschappelijk Onderzoek (#G012500), Associazone Italiana per la Ricerca sul Cancro, Istituto Superiore di Sanità (Programma Nazionale AIDS 1998), Deutsche Forschungsgemeinschaft (SFB451/B1, SFB497/C1, SPP1069/Do688/1-1 and Wa734/6-2), Hauptabteilung fur die Sicherheit der Kernanlagen der Schweiz (#65680), Ulm University Medical Center (#P.570) and the European Molecular Biology Organization (fellowship to M.A). David Communi and Didier Communi are Research Associates at the Fonds National pour la Recherche Scientifique.

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Author notes

  1. Monica Autiero, Johannes Waltenberger and Didier Communi: These authors contributed equally to this work.

Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, B-3000, Belgium

    Monica Autiero, Didier Communi, Lieve Moons, Diether Lambrechts, Stephane Plaisance, Maria De Mol, Mieke Dewerchin, Paul Van Hummelen, Désiré Collen, Edward M Conway & Peter Carmeliet

  2. Department of Internal Medicine II, Ulm University Medical Center, Ulm, D-8908, Germany

    Johannes Waltenberger, Andrea Kranz, Jens Kroll, Stefanie Kliche, Guido Fellbrich, Ulrike Mayr-Beyrle & Saskia Dombrowski

  3. Haemobiology Department, Sanofi, Toulouse, 31036, Cedex, France

    Françoise Bono & Jean-Marc Herbert

  4. Paul Scherrer Institute, Laboratory of Biomolecular Research Molecular Cell Biology, 5232 Villigen-PSI, Switzerland

    Kurt Ballmer-Hofer

  5. Geymonat SpA, Anagni, 03012, Italy

    Domenico Maglione

  6. Cellular Neurobiology Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, K1A 0R6, Ontario, Canada

    Danica Stanimirovic

  7. Division of Molecular Microbiology, Biozentrum of the University of Basel, Basel, CH-4056, Switzerland

    Christoph Dehio

  8. ImClone Systems Inc, New York, 10014, New York, USA

    Daniel J Hicklin

  9. Istituto Internazionale di Genetica e Biofisica, CNR, Naples, 80125, Italy

    Graziella Persico

  10. Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Free University of Brussels, Brussels, B-1070

    David Communi

  11. Department of Genetics, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Masabumi Shibuya

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Correspondence to Peter Carmeliet.

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Autiero, M., Waltenberger, J., Communi, D. et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9, 936–943 (2003). https://doi.org/10.1038/nm884

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