Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity
Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity
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DOI：
10.1182/blood-2007-04-084269
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Merkulova-Rainon, Tatyana
中科院分区：
文献类型：
--
作者：
Sulpice, Eric;Plouet, Jean;Merkulova-Rainon, Tatyana
神经纤毛蛋白-1和-2（NRP 1和NRP 2）是与2种类型的配体相互作用的跨膜糖蛋白：III类信号蛋白和VEGF家族的几个成员，血管和淋巴管生长的主要调节剂。我们在这里表明，NRP 1和NRP 2也可以结合肝细胞生长因子（HGF）。HGF是一种多效性细胞因子和有效的促血管生成分子，其通过与c-met受体结合而作用于其靶细胞。我们发现HGF的N端结构域参与了与神经纤毛蛋白的相互作用。我们证明，在人脐静脉内皮细胞（HUVECs）中，通过RNA干扰使NRP 1或NRP 2失效，降低了HGF诱导的c-met磷酸化以及VEGF-A（165）和HGF介导的细胞内信号传导。因此，用阻断抗体破坏NRP 1或NRP 2与VEGF-A（165）或HGF的结合，降低了内皮细胞的增殖和迁移。如果VEGF-A（165）或HGF与NRP 1和NRP 2的结合被破坏，这种作用可能会进一步增强。使用小鼠Matrigel模型，我们证明了NRPi对于体内HGF介导的血管生成是必需的。我们的研究结果表明，在内皮细胞中，NRP 1和NRP 2作为促血管生成辅助受体发挥作用，增强至少2种主要促血管生成细胞因子VEGF-A（165）和HGF的活性。
Neuropilin-1 and -2 (NRP1 and NRP2) are the transmembrane glycoproteins interacting with 2 types of ligands: class III semaphorins and several members of the VEGF family, the main regulators of blood and lymphatic vessel growth. We show here that both NRP1 and NRP2 can also bind hepatocyte growth factor (HGF). HGF is a pleiotropic cytokine and potent proangiogenic molecule that acts on its target cells by binding to the c-met receptor. We found that the N-terminal domain of HGF is involved in the interaction with neuropilins. We demonstrated that invalidation of NRP1 or NRP2 by RNA interference in human umbilical vein endothelial cells (HUVECs) decreased HGF-induced c-met phosphorylation and VEGF-A(165)- and HGF-mediated intracellular signaling. Accordingly, the disruption of NRP1 or NRP2 binding to VEGF-A(165) or HGF with a blocking antibody, decreased the proliferation and migration of endothelial cells. This effect may be further enhanced if VEGF-A(165) or HGF binding to both NRP1 and NRP2 was disrupted. Using a mouse Matrigel model, we demonstrated that NRPi is essential for HGF-mediated angiogenesis in vivo. Our results suggest that, in endothelial cells, both NRP1 and NRP2 function as proangiogenic coreceptors, potentiating the activity of at least 2 major proangiogenic cytokines, VEGF-A(165) and HGF.