Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono 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 K H, Foidart J M, Schaper W, Charnock-Jones D S, Hicklin D J, Herbert J M, Collen D, Persico M G
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
Nat Med. 2001 May;7(5):575-83. doi: 10.1038/87904.
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.
血管内皮生长因子（VEGF）通过激活VEGF受体2（VEGFR-2）来刺激血管生成。其同源物胎盘生长因子（PlGF）的作用尚不清楚。VEGF和PlGF都能与VEGF受体1（VEGFR-1）结合，但作为可溶性或膜结合型存在的VEGFR-1在血管生成过程中是一种惰性诱饵还是PlGF的信号受体尚不清楚。在此，我们报告，PlGF缺陷（Pgf-/-）的小鼠胚胎血管生成不受影响。VEGFR-1的另一种配体VEGF-B不能挽救Pgf-/-小鼠的发育。然而，PlGF的缺失会损害缺血、炎症、伤口愈合和癌症期间的血管生成、血浆外渗和侧支生长。野生型骨髓移植挽救了Pgf-/-小鼠受损的血管生成和侧支生长，表明PlGF可能通过动员骨髓来源的细胞促进了成体中的血管生长。PlGF与VEGF之间的协同作用是特异性的，因为PlGF缺陷会损害对VEGF的反应，但不影响对bFGF或组胺的反应。鉴于抗VEGFR-1抗体和一种Src激酶抑制剂可阻断内皮细胞对PlGF或VEGF/PlGF的反应，因此PlGF可激活VEGFR-1。在许多病理疾病的“血管生成开关”过程中，内皮细胞通过上调PlGF和VEGFR-1的信号亚型来增强其对VEGF的反应性。
