Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1.
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.
Autiero
Monica
M
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, B-3000, Belgium.
Waltenberger
Johannes
J
Communi
Didier
D
Kranz
Andrea
A
Moons
Lieve
L
Lambrechts
Diether
D
Kroll
Jens
J
Plaisance
Stephane
S
De Mol
Maria
M
Bono
Françoise
F
Kliche
Stefanie
S
Fellbrich
Guido
G
Ballmer-Hofer
Kurt
K
Maglione
Domenico
D
Mayr-Beyrle
Ulrike
U
Dewerchin
Mieke
M
Dombrowski
Saskia
S
Stanimirovic
Danica
D
Van Hummelen
Paul
P
Dehio
Christoph
C
Hicklin
Daniel J
DJ
Persico
Graziella
G
Herbert
Jean-Marc
JM
Communi
David
D
Shibuya
Masabumi
M
Collen
Désiré
D
Conway
Edward M
EM
Carmeliet
Peter
P
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
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