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

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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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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