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

Monica Autiero; Johannes Waltenberger; Didier Communi; Andrea Kranz; Lieve Moons; Diether Lambrechts; Jens Kroll; Stephane Plaisance; Maria De Mol; Françoise Bono; Stefanie Kliche; Guido Fellbrich; Kurt Ballmer-Hofer; Domenico Maglione; Ulrike Mayr-Beyrle; Mieke Dewerchin; Saskia Dombrowski; Danica Stanimirovic; Paul Van Hummelen; Christoph Dehio; Daniel J Hicklin; Graziella Persico; Jean-Marc Herbert; David Communi; Masabumi Shibuya; Désiré Collen; Edward M Conway; Peter Carmeliet

doi:10.1038/nm884

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

Nat Med. 2003 Jul;9(7):936-43. doi: 10.1038/nm884.

Affiliation

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

PMID: 12796773
DOI: 10.1038/nm884

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Dimerization
Endothelial Growth Factors / metabolism
Endothelial Growth Factors / pharmacology
Endothelium, Vascular / cytology
Endothelium, Vascular / drug effects
Endothelium, Vascular / physiology
Enzyme Activation
Gene Expression Profiling
Humans
Intercellular Signaling Peptides and Proteins / metabolism
Intercellular Signaling Peptides and Proteins / pharmacology
Lymphokines / metabolism
Lymphokines / pharmacology
Mice
Myocardial Ischemia / metabolism
Myocardial Ischemia / pathology
Neovascularization, Pathologic / metabolism
Neovascularization, Physiologic / drug effects
Phosphorylation
Placenta Growth Factor
Pregnancy Proteins / metabolism*
Pregnancy Proteins / pharmacology
Receptor Cross-Talk / physiology*
Signal Transduction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-1 / metabolism*
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Vascular Endothelial Growth Factors
Viral Proteins / metabolism
Viral Proteins / pharmacology

Substances

Endothelial Growth Factors
Intercellular Signaling Peptides and Proteins
Lymphokines
PGF protein, human
Pgf protein, mouse
Pregnancy Proteins
VEGF-like protein, Orf virus
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Viral Proteins
Placenta Growth Factor
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2