Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions

被引:1314
作者
Carmeliet, P [1 ]
Moons, L
Luttun, A
Vincenti, V
Compernolle, V
De Mol, M
Wu, Y
Bon, F
Devy, L
Beck, H
Scholz, D
Acker, T
DiPalma, T
Dewerchin, M
Noel, A
Stalmans, I
Barra, A
Blacher, S
Vandendriessche, T
Ponten, A
Eriksson, U
Plate, KH
Foidart, JM
Schaper, W
Charnock-Jones, DS
Hicklin, DJ
Herbert, JM
Collen, D
Persico, MG
机构
[1] Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, Louvain, Belgium
[2] CNR, Ist Int Genet & Biofis, I-80125 Naples, Italy
[3] ImClone Syst, New York, NY USA
[4] Sanofi Synthelabo, Cardiovasc Thrombosis Res Dept, Toulouse, France
[5] Univ Liege, Lab Tumor & Dev Biol, B-4000 Sart Tilman Par Liege, Belgium
[6] FAU Erlangen Nurnberg, Dept Neuropathol, Erlangen, Germany
[7] Max Planck Inst, Dept Expt Cardiol, Bad Nauheim, Germany
[8] Univ Cambridge, Dept Obstet & Gynaecol, Reprod Mol Res Grp, Cambridge, England
[9] Ludwig Inst Canc Res, S-10401 Stockholm, Sweden
关键词
D O I
10.1038/87904
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PIGF), remains unknown. Both VEGF and PIGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VECFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PIGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PIGF (Pgf(-/-)). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf(-/-) mice. However, loss of PIGF 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 PIGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PIGF and VEGF was specific, as PIGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VECFR-1 was activated by PIGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PIGF or VEGF/PIGF. By upregulating PIGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.
引用
收藏
页码:575 / 583
页数:9
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