title: Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1.
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.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, B-3000, Belgium.
authors.forename: Monica
authors.initials: M
authors.lastname: Autiero
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Didier
authors.initials: D
authors.lastname: Communi
authors.forename: Andrea
authors.initials: A
authors.lastname: Kranz
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
authors.forename: Stephane
authors.initials: S
authors.lastname: Plaisance
authors.forename: Maria
authors.initials: M
authors.lastname: De Mol
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.forename: Guido
authors.initials: G
authors.lastname: Fellbrich
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.forename: Domenico
authors.initials: D
authors.lastname: Maglione
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayr-Beyrle
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Saskia
authors.initials: S
authors.lastname: Dombrowski
authors.forename: Danica
authors.initials: D
authors.lastname: Stanimirovic
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehio
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Graziella
authors.initials: G
authors.lastname: Persico
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: David
authors.initials: D
authors.lastname: Communi
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism* / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; C084758:VEGF-like protein, Orf virus; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2