Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions
Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions
复制标题
DOI：
10.1038/87904
复制
发表时间：
2001-05-01
期刊：
影响因子：
82.9
通讯作者：
Persico, MG
中科院分区：
文献类型：
--
作者：
Carmeliet, P;Moons, L;Persico, MG
血管内皮生长因子（VEGF）通过激活VEGF受体-2（VEGFR-2）刺激血管生成。其同系物胎盘生长因子（PlGF）的作用仍然未知。VEGF和PIGF都与VEGF受体-1（VEGFR-1）结合，但目前尚不清楚VECFR-1（以可溶性或膜结合型存在）是血管生成过程中PIGF的惰性诱饵还是信号受体。在这里，我们报告，胚胎血管生成的小鼠不受PIGF（Pgf（-/-））的缺陷。VEGF-B是VEGFR-1的另一种配体，在Pgf（-/-）小鼠中不能挽救发育。然而，PIGF的损失损害了局部缺血、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PIGF可能通过动员骨髓源性细胞促进了成人血管生长。PIGF和VEGF之间的协同作用是特异性的，因为PIGF缺乏会损害对VEGF的反应，但不会损害对bFGF或组胺的反应。考虑到抗VEGFR-1抗体和Src-激酶抑制剂阻断了对PIGF或VEGF/PIGF的内皮应答，VECFR-1被PIGF激活。通过上调PIGF和VEGFR-1的信号亚型，内皮细胞在许多病理性疾病中的“血管生成转换”期间放大了它们对VEGF的反应性。
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.