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Article
Nature Medicine  9, 936 - 943 (2003)
Published online: 8 June 2003; | doi:10.1038/nm884

Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1

Monica Autiero1, 12, Johannes Waltenberger2, 12, Didier Communi1, 12, Andrea Kranz2, Lieve Moons1, Diether Lambrechts1, Jens Kroll2, Stephane Plaisance1, Maria De Mol1, Françoise Bono3, Stefanie Kliche2, Guido Fellbrich2, Kurt Ballmer-Hofer4, Domenico Maglione5, Ulrike Mayr-Beyrle2, Mieke Dewerchin1, Saskia Dombrowski2, Danica Stanimirovic6, Paul Van Hummelen1, Christoph Dehio7, Daniel J Hicklin8, Graziella Persico9, Jean-Marc Herbert3, David Communi10, Masabumi Shibuya11, Désiré Collen1, Edward M Conway1 & Peter Carmeliet1

1  The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, B-3000, Belgium.

2  Department of Internal Medicine II, Ulm University Medical Center, Ulm, D-8908, Germany.

3  Haemobiology Department, Sanofi, Cedex 31036, Toulouse, France.

4  Paul Scherrer Institute, Laboratory of Biomolecular Research Molecular Cell Biology, 5232 Villigen-PSI, Switzerland.

5  Geymonat SpA, 03012 Anagni, Italy.

6  Cellular Neurobiology Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada.

7  Division of Molecular Microbiology, Biozentrum of the University of Basel, Basel, CH-4056, Switzerland.

8  ImClone Systems Inc, New York, New York 10014, USA.

9  Istituto Internazionale di Genetica e Biofisica, CNR, 80125 Naples, Italy.

10  Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Free University of Brussels, B-1070 Brussels.

11  Department of Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

12  These authors contributed equally to this work.

Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.be
Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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