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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

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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.
The alternative text for this image may have been generated using AI.
Figure 2: Impaired retinal and myocardial angiogenesis in Pgf−/− mice.
The alternative text for this image may have been generated using AI.
Figure 3: Impaired pathological arteriogenesis in Pgf−/− mice.
The alternative text for this image may have been generated using AI.
Figure 4: Impaired collateral growth in Pgf−/− mice.
The alternative text for this image may have been generated using AI.
Figure 5: Modulation of permeability and of VEGF-response by PlGF.
The alternative text for this image may have been generated using AI.

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References

  1. Dvorak, H.F. VPF/VEGF and the angiogenic response. Semin. Perinatol. 24, 75–78 (2000).

    Article  CAS  Google Scholar 

  2. Ferrara, N. Vascular endothelial growth factor: molecular and biological aspects. Curr. Top. Microbiol. Immunol. 237, 1–30 (1999).

    CAS  PubMed  Google Scholar 

  3. Persico, M.G., Vincenti, V. & DiPalma, T. Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr. Top. Microbiol. Immunol. 237, 31–40 (1999).

    CAS  PubMed  Google Scholar 

  4. Achen, M.G., Gad, J.M., Stacker, S.A. & Wilks, A.F. Placenta growth factor and vascular endothelial growth factor are co-expressed during early embryonic development. Growth Factors 15, 69–80 (1997).

    Article  CAS  Google Scholar 

  5. Monsky, W.L. et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59, 4129–4135 (1999).

    CAS  PubMed  Google Scholar 

  6. Park, J.E., Chen, H.H., Winer, J., Houck, K.A. & Ferrara, N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J. Biol. Chem. 269, 25646–25654 (1994).

    CAS  PubMed  Google Scholar 

  7. Viglietto, G. et al. Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor. Oncogene 13, 577–587 (1996).

    CAS  PubMed  Google Scholar 

  8. Nomura, M. et al. Placenta growth factor (PlGF) mRNA expression in brain tumors. J. Neurooncol. 40, 123–30 (1998).

    Article  CAS  Google Scholar 

  9. Neufeld, G., Cohen, T., Gengrinovitch, S. & Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 (1999).

    Article  CAS  Google Scholar 

  10. Shibuya, M., Ito, N. & Claesson-Welsh, L. Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr. Top. Microbiol. Immunol. 237, 59–83 (1999).

    CAS  PubMed  Google Scholar 

  11. Fong, G.H., Rossant, J., Gertsenstein, M. & Breitman, M.L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

    Article  CAS  Google Scholar 

  12. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl. Acad. Sci. USA 95, 9349–9354 (1998).

    Article  CAS  Google Scholar 

  13. Kendall, R.L., Wang, G. & Thomas, K.A. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem. Biophys. Res. Commun. 226, 324–328 (1996).

    Article  CAS  Google Scholar 

  14. Clark, D.E. et al. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol. Reprod. 59, 1540–1548 (1998).

    Article  CAS  Google Scholar 

  15. Landgren, E., Schiller, P., Cao, Y. & Claesson-Welsh, L. Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-γ and migration of endothelial cells expressing Flt 1. Oncogene 16, 359–367 (1998).

    Article  CAS  Google Scholar 

  16. Cao, Y., Linden, P., Shima, D., Browne, F. & Folkman, J. In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J. Clin. Invest. 98, 2507–2511 (1996).

    Article  CAS  Google Scholar 

  17. DiSalvo, J. et al. Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer. J. Biol. Chem. 270, 7717–7723 (1995).

    Article  CAS  Google Scholar 

  18. Olofsson, B., Jeltsch, M., Eriksson, U. & Alitalo, K. Current biology of VEGF-B and VEGF-C. Curr. Opin. Biotechnol. 10, 528–535 (1999).

    Article  CAS  Google Scholar 

  19. Aase, K. et al. VEGF-B deficient mice display an atrial conduction defect. Circulation (in the press).

  20. Hatva, E. et al. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am. J. Pathol. 148, 763–775 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Takahashi, A. et al. Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. Biochem. Biophys. Res. Commun. 257, 855–859 (1999).

    Article  CAS  Google Scholar 

  22. Viglietto, G. et al. Upregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PlGF) associated with malignancy in human thyroid tumors and cell lines. Oncogene 11, 1569–1579 (1995).

    CAS  PubMed  Google Scholar 

  23. Simpson, D.A. et al. Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. Biochem. Biophys. Res. Commun. 262, 333–340 (1999).

    Article  CAS  Google Scholar 

  24. Khaliq, A. et al. Increased expression of placenta growth factor in proliferative diabetic retinopathy. Lab. Invest. 78, 109–116 (1998).

    CAS  PubMed  Google Scholar 

  25. Heymans, S. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nature Med. 5, 1135–1142 (1999).

    Article  CAS  Google Scholar 

  26. Arras, M. et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J. Clin. Invest. 101, 40–50 (1998).

    Article  CAS  Google Scholar 

  27. Clauss, M. et al. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271, 17629–17634 (1996).

    Article  CAS  Google Scholar 

  28. Rafii, S. Circulating endothelial precursors: mystery, reality, and promise. J. Clin. Invest. 105, 17–19 (2000).

    Article  CAS  Google Scholar 

  29. Kalka, C. et al. Vascular endothelial growth factor (165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ. Res. 86, 1198–1202 (2000).

    Article  CAS  Google Scholar 

  30. Eliceiri, B.P. et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell. 4, 915–924 (1999).

    Article  CAS  Google Scholar 

  31. He, H. et al. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c–Src. J. Biol. Chem. 274, 25130–25135 (1999).

    Article  CAS  Google Scholar 

  32. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).

    Article  CAS  Google Scholar 

  33. Migdal, M. et al. Neuropilin-1 is a placenta growth factor-2 receptor. J. Biol. Chem. 273, 22272–22278 (1998).

    Article  CAS  Google Scholar 

  34. Gerber, H.P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149–1159 (1999).

    CAS  Google Scholar 

  35. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    Article  CAS  Google Scholar 

  36. Witte, L. et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 17, 155–161 (1998).

    Article  CAS  Google Scholar 

  37. Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 (1999).

    Article  CAS  Google Scholar 

  38. Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495–502 (1999).

    Article  CAS  Google Scholar 

  39. Passaniti, A. et al. A simple, quantitative method for assessing aniogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab. Invest. 67, 519–528 (1992).

    CAS  PubMed  Google Scholar 

  40. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  Google Scholar 

  41. Ryan, H.E. et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010–4015 (2000).

    CAS  Google Scholar 

  42. Frank, S. et al. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J. Biol. Chem. 270, 12607–12613 (1995).

    Article  CAS  Google Scholar 

  43. Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460–463 (2000).

    Article  CAS  Google Scholar 

  44. Vicaut, E. & Stucker, O. An intact cremaster muscle preparation for studying the microcirculation by in vivo microscopy. Microvasc. Res. 39, 120–122 (1990).

    Article  CAS  Google Scholar 

  45. Nicosia, R.F. & Villaschi, S. Autoregulation of angiogenesis by cells of the vessel wall. Int. Rev. Cytol. 185, 1–43 (1999).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Peter Carmeliet
  2. Lieve Moons
  3. Aernout Luttun
  4. Valeria Vincenti
  5. Veerle Compernolle
  6. Maria De Mol
  7. Yan Wu
  8. Françoise Bono
  9. Laetitia Devy
  10. Heike Beck
  11. Dimitri Scholz
  12. Till Acker
  13. Tina DiPalma
  14. Mieke Dewerchin
  15. Agnes Noel
  16. Ingeborg Stalmans
  17. Adriano Barra
  18. Sylvia Blacher
  19. Thierry Vandendriessche
  20. Annica Ponten
  21. Ulf Eriksson
  22. Karl H. Plate
  23. Jean-Michel Foidart
  24. Wolfgang Schaper
  25. D. Stephen Charnock-Jones
  26. Daniel J. Hicklin
  27. Jean-Marc Herbert
  28. Désiré Collen
  29. M. Graziella Persico

Corresponding author

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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  • DOI: https://doi.org/10.1038/87904

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