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Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions

Nature Medicine volume 7, pages 575–583 (2001)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf−/−). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf−/− mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf−/− mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow–derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

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Figure 1: Normal vascular development but impaired tumor angiogenesis in Pgf−/− mice.
Figure 2: Impaired retinal and myocardial angiogenesis in Pgf−/− mice.
Figure 3: Impaired pathological arteriogenesis in Pgf−/− mice.
Figure 4: Impaired collateral growth in Pgf−/− mice.
Figure 5: Modulation of permeability and of VEGF-response by PlGF.

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Acknowledgements

We thank P. Schaeffer, K. Bijnens, A. Bouché, S. De Cat, M. De Mol, K. De Roover, E. Gils, B. Hermans, S. Jansen, L. Kieckens, A. Manderveld, K. Maris, A. Sahli, T. Vancoetsem, A. Vandenhoeck, P. Van Wesemael and S. Wyns for assistance. This work was supported in part by the European Community (Biomed BMH4-CT98-3380), Actie Levenslijn (#7.0019.98), F.W.O. (G012500), AIRC and ISS (Programma Nazionale AIDS 1998), the Deutsche Krebshilfe 10-1302-Ri 3 and BMBF 01 KV 9922/6. A. Noel and L. Devy are supported by the F.N.R.S.

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Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium

    Peter Carmeliet, Lieve Moons, Aernout Luttun, Veerle Compernolle, Maria De Mol, Mieke Dewerchin, Ingeborg Stalmans, Thierry Vandendriessche & Désiré Collen

  2. Istituto Internazionale di Genetica e Biofisica, CNR, Naples, Italy

    Valeria Vincenti, Tina DiPalma, Adriano Barra & M. Graziella Persico

  3. ImClone Systems, New York, New York, USA

    Yan Wu & Daniel J. Hicklin

  4. Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse, France

    Françoise Bono & Jean-Marc Herbert

  5. Laboratory of Tumor and Developmental Biology, University Liège, Sart-Tilman, Belgium

    Laetitia Devy, Agnes Noel, Sylvia Blacher & Jean-Michel Foidart

  6. Department of Neuropathology, FAU Erlangen-Nürnberg, Erlangen, Germany

    Heike Beck, Till Acker & Karl H. Plate

  7. Department of Experimental Cardiology, Max-Planck-Institute, Nauheim, Germany

    Dimitri Scholz & Wolfgang Schaper

  8. Department Obstetrics & Gynaecology, Reproductive Molecular Research Group, University of Cambridge, Cambridge, UK

    D. Stephen Charnock-Jones

  9. Ludwig Institute for Cancer Research, Stockholm, Sweden

    Annica Ponten & Ulf Eriksson

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Correspondence to Peter Carmeliet.

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Carmeliet, P., Moons, L., Luttun, A. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7, 575–583 (2001). https://doi.org/10.1038/87904

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