The Basis for the Distinct Biological Activities of Vascular Endothelial Growth Factor Receptor-1 Ligands
The Basis for the Distinct Biological Activities of Vascular Endothelial Growth Factor Receptor-1 Ligands
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DOI：
10.1126/scisignal.2003905
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发表时间：
2013-07-02
影响因子：
7.3
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
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作者：
Anisimov, Andrey;Leppanen, Veli-Matti;Alitalo, Kari
血管内皮生长因子（VEGF）通过VEGF受体（VEGFRs）调节血液和淋巴管的发育。VEGFR免疫球蛋白同源结构域2（D2）对于配体结合至关重要，D3提供了额外的相互作用位点。VEGF-B和胎盘生长因子（PlGF）以高亲和力结合VEGFR-1，但在大多数组织中只有PlGF具有血管生成作用。我们表明，与其他血管内皮生长因子不同，VEGF-B不需要D3相互作用即可实现高亲和力结合。VEGF-B与PIGF衍生的L1环（B-L1（P））刺激VEGFR-1活性，而PIGF与VEGF-B衍生的L1环（P-L1（B））不刺激。与P-L1（B）和VEGF-B不同，B-L1（P）和PlGF在小鼠骨骼肌中也具有血管生成作用。此外，B-L1（P）还与VEGFR-2结合并激活下游信号传导。这些结果确立了L1介导的D3相互作用在内皮细胞中的VEGFR活化中的作用，并表明VEGF-B是一种高亲和力的VEGFR-1配体，与PlGF不同，它不能有效地诱导VEGFR-1下游的信号传导。
Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high affinity, but only PlGF is angiogenic in most tissues. We show that VEGF-B, unlike other VEGFs, did not require D3 interactions for high-affinity binding. VEGF-B with a PlGF-derived L1 loop (B-L1(P)) stimulated VEGFR-1 activity, whereas PlGF with a VEGF-B-derived L1 loop (P-L1(B)) did not. Unlike P-L1(B) and VEGF-B, B-L1(P) and PlGF were also angiogenic in mouse skeletal muscle. Furthermore, B-L1(P) also bound to VEGFR-2 and activated downstream signaling. These results establish a role for L1-mediated D3 interactions in VEGFR activation in endothelial cells and indicate that VEGF-B is a high-affinity VEGFR-1 ligand that, unlike PlGF, cannot efficiently induce signaling downstream of VEGFR-1.