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

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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.


  • Peter Carmeliet
  • Lieve Moons
  • Aernout Luttun
  • Valeria Vincenti
  • Veerle Compernolle
  • Maria De Mol
  • Yan Wu
  • Françoise Bono
  • Laetitia Devy
  • Heike Beck
  • Dimitri Scholz
  • Till Acker
  • Tina DiPalma
  • Mieke Dewerchin
  • Agnes Noel
  • Ingeborg Stalmans
  • Adriano Barra
  • Sylvia Blacher
  • Thierry Vandendriessche
  • Annica Pontén
  • Och 9 andra
  • Ulf Eriksson
  • Karl H. Plate
  • Jean-Michel Foidart
  • Wolfgang Schaper
  • D. Stephen Charnock-Jones
  • Daniel J. Hicklin
  • Jean-Marc Herbert
  • Désiré Collen
  • M. Graziella Persico
Enheter & grupper

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Sidor (från-till)575-583
TidskriftNature Medicine
Utgåva nummer5
StatusPublished - 2001
Peer review utfördJa