Nature Medicine
7, 575 - 583 (2001)
doi:10.1038/87904
Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditionsPeter Carmeliet1, Lieve Moons1, Aernout Luttun1, Valeria Vincenti2, Veerle Compernolle1, Maria De Mol1, Yan Wu3, Françoise Bono4, Laetitia Devy5, Heike Beck6, Dimitri Scholz7, Till Acker6, Tina DiPalma2, Mieke Dewerchin1, Agnes Noel5, Ingeborg Stalmans1, Adriano Barra2, Sylvia Blacher5, Thierry Vandendriessche1, Annica Ponten9, Ulf Eriksson9, Karl H. Plate6, Jean-Michel Foidart5, Wolfgang Schaper7, D. Stephen Charnock-Jones8, Daniel J. Hicklin3, Jean-Marc Herbert4, Désiré Collen1
& M. Graziella Persico21
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium
2
Istituto Internazionale di Genetica e Biofisica, CNR, Naples, Italy
3
ImClone Systems, New York, New York, USA
4
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse, France
5
Laboratory of Tumor and Developmental Biology, University Liège, Sart-Tilman, Belgium
6
Department of Neuropathology, FAU Erlangen-Nürnberg, Erlangen, Germany
7
Department of Experimental Cardiology, Max-Planck-Institute, Nauheim, Germany
8
Reproductive Molecular Research Group, Department Obstetrics & Gynaecology, University of Cambridge, Cambridge, UK
9
Ludwig Institute for Cancer Research, Stockholm, Sweden
Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beVascular 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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