VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism.
Two signaling receptors for vascular endothelial growth factor (VEGF) in the vasculature are known with not yet well-understood roles in collateral vessel growth (arteriogenesis). In this study, we examined the involvement of the two VEGF receptors in arteriogenesis. Therefore, we used the VEGF homologue placenta growth factor (PlGF), which only binds to VEGFR-1 and VEGF-E, which only recognizes VEGFR-2. These peptides were locally infused over 7 days after ligation of the femoral artery in the rabbit. Evaluation of collateral growth by determining collateral conductance and angiographic scores demonstrated that the VEGFR-1-specific PlGF contributed significantly more to arteriogenesis than the VEGFR-2 specific VEGF-E. The combination of VEGF-E and PlGF did not exceed the effect of PlGF alone, indicating that cooperation of the two VEGF receptors in endothelial cell signaling is not required for arteriogenesis. In an in vitro model of angiogenesis, VEGF and VEGF-E were comparably active, whereas PlGF displayed no activity when given alone and did not further increase the effects of VEGF or VEGF-E. However, PlGF was as potent as VEGF when monocyte activation was assessed by monitoring integrin surface expression. In addition, accumulation of activated monocytes/macrophages in the periphery of collateral vessels in PlGF-treated animals was observed. Furthermore, in monocyte-depleted animals, the ability of PlGF to enhance collateral growth in the rabbit model and to rescue impaired arteriogenesis in PlGF gene-deficient mice was abrogated. Together, these data indicate that the arteriogenic activity observed with the VEGFR-1-specific PlGF is caused by its monocyte-activating properties.
Pipp
Frederic
F
Max-Planck-Institute for Physiological and Clinical Research, Dept of Experimental Cardiology, Benekestr. 2, 61231 Bad Nauheim, Germany. f.pipp@kerckhoff.mpg.de
Heil
Matthias
M
Issbrücker
Katja
K
Ziegelhoeffer
Tibor
T
Martin
Sandra
S
van den Heuvel
Joop
J
Weich
Herbert
H
Fernandez
Borja
B
Golomb
Gershon
G
Carmeliet
Peter
P
Schaper
Wolfgang
W
Clauss
Matthias
M
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D005263:Femoral Artery / Q000601:surgery; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008026:Ligation; D008222:Lymphokines / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins / Q000494:pharmacology
D016228:Endothelial Growth Factors; D016023:Integrins; 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