Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.
Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.
Carmeliet
P
P
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium. peter.carmeliet@med.kuleuven.ac.be
Moons
L
L
Luttun
A
A
Vincenti
V
V
Compernolle
V
V
De Mol
M
M
Wu
Y
Y
Bono
F
F
Devy
L
L
Beck
H
H
Scholz
D
D
Acker
T
T
DiPalma
T
T
Dewerchin
M
M
Noel
A
A
Stalmans
I
I
Barra
A
A
Blacher
S
S
VandenDriessche
T
T
Ponten
A
A
Eriksson
U
U
Plate
K H
KH
Foidart
J M
JM
Schaper
W
W
Charnock-Jones
D S
DS
Hicklin
D J
DJ
Herbert
J M
JM
Collen
D
D
Persico
M G
MG
D000818:Animals; D001483:Base Sequence; D002199:Capillary Permeability; D017931:DNA Primers; D005314:Embryonic and Fetal Development; D016228:Endothelial Growth Factors / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D010949:Plasma; D011257:Pregnancy Proteins / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000502:physiology
D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor