Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation
Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation
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DOI：
10.1126/scisignal.aad3812
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发表时间：
2016-04-26
影响因子：
7.3
通讯作者：
Augustin, Hellmut G.
中科院分区：
文献类型：
--
作者：
Roth, Lise;Prahst, Claudia;Augustin, Hellmut G.
神经纤毛蛋白-1（NRP 1）调节发育和病理性血管生成、动脉生成和血管通透性，作为脑信号蛋白3A（Sema 3A）和血管内皮生长因子A（VEGF-A（165））的165个氨基酸亚型的共受体。NRP 1也是CendR肽的受体，CendR肽是一类具有特定R-x-x-R羧基末端基序的细胞和组织穿透肽。由于NRP 1的胞质结构域缺乏催化活性，NRP 1主要被认为是通过募集和结合其他受体来发挥作用。我们在这里报告，NRP 1细胞内域介导血管通透性。用VEGF-A（165）、配体阻断抗体和CendR肽刺激导致内皮细胞单层中细胞-细胞接触处的NRP 1积累，增加体外细胞渗透性和体内血管渗漏。生物化学分析、VEGF受体-2（VEGFR-2）沉默和特异性VEGFR阻断剂的使用确定了由CendR肽和抗体诱导的作用不依赖于VEGFR-2。此外，在表达缺乏胞质结构域的突变型NRP 1的小鼠中的渗漏测定显示，该结构域是NRP 1诱导的体内血管通透性所需的。因此，这些数据定义了由NRP 1介导但独立于VEGFR-2活化的血管通透性途径。
Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A(165)). NRP1 is also the receptor for the CendR peptides, a class of cell-and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A(165), a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.