Pipp Frederic, Heil Matthias, Issbrücker Katja, Ziegelhoeffer Tibor, Martin Sandra, van den Heuvel Joop, Weich Herbert, Fernandez Borja, Golomb Gershon, Carmeliet Peter, Schaper Wolfgang, Clauss Matthias
Max-Planck-Institute for Physiological and Clinical Research, Dept of Experimental Cardiology, Benekestr. 2, 61231 Bad Nauheim, Germany.
Circ Res. 2003 Mar 7;92(4):378-85. doi: 10.1161/01.RES.0000057997.77714.72. Epub 2003 Jan 23.
Two signaling receptors for vascular endothelial growth factor (VEGF) in the vasculature are known with not yet well-understood roles in collateral vessel growth (arteriogenesis). In this study, we examined the involvement of the two VEGF receptors in arteriogenesis. Therefore, we used the VEGF homologue placenta growth factor (PlGF), which only binds to VEGFR-1 and VEGF-E, which only recognizes VEGFR-2. These peptides were locally infused over 7 days after ligation of the femoral artery in the rabbit. Evaluation of collateral growth by determining collateral conductance and angiographic scores demonstrated that the VEGFR-1-specific PlGF contributed significantly more to arteriogenesis than the VEGFR-2 specific VEGF-E. The combination of VEGF-E and PlGF did not exceed the effect of PlGF alone, indicating that cooperation of the two VEGF receptors in endothelial cell signaling is not required for arteriogenesis. In an in vitro model of angiogenesis, VEGF and VEGF-E were comparably active, whereas PlGF displayed no activity when given alone and did not further increase the effects of VEGF or VEGF-E. However, PlGF was as potent as VEGF when monocyte activation was assessed by monitoring integrin surface expression. In addition, accumulation of activated monocytes/macrophages in the periphery of collateral vessels in PlGF-treated animals was observed. Furthermore, in monocyte-depleted animals, the ability of PlGF to enhance collateral growth in the rabbit model and to rescue impaired arteriogenesis in PlGF gene-deficient mice was abrogated. Together, these data indicate that the arteriogenic activity observed with the VEGFR-1-specific PlGF is caused by its monocyte-activating properties.
已知脉管系统中血管内皮生长因子（VEGF）的两种信号受体在侧支血管生长（动脉生成）中的作用尚未完全明确。在本研究中，我们检测了这两种VEGF受体在动脉生成中的作用。因此，我们使用了VEGF同源物胎盘生长因子（PlGF），其仅与VEGFR-1结合，以及VEGF-E，其仅识别VEGFR-2。在兔股动脉结扎后7天内局部注入这些肽。通过测定侧支血管传导率和血管造影评分来评估侧支血管生长，结果表明，VEGFR-1特异性的PlGF对动脉生成的贡献显著大于VEGFR-2特异性的VEGF-E。VEGF-E和PlGF的联合作用未超过单独使用PlGF的效果，这表明动脉生成不需要两种VEGF受体在内皮细胞信号传导中的协同作用。在血管生成的体外模型中，VEGF和VEGF-E具有相当的活性，而单独给予PlGF时无活性，且不会进一步增强VEGF或VEGF-E的作用。然而，通过监测整合素表面表达评估单核细胞活化时，PlGF与VEGF一样有效。此外，在接受PlGF治疗的动物侧支血管周围观察到活化的单核细胞/巨噬细胞聚集。此外，在单核细胞耗竭的动物中，PlGF增强兔模型侧支血管生长和挽救PlGF基因缺陷小鼠受损动脉生成的能力被消除。总之，这些数据表明，VEGFR-1特异性的PlGF所观察到的动脉生成活性是由其单核细胞活化特性引起的。
