Neuropilin-1 regulates vascular endothelial growth factor-mediated endothelial permeability
Neuropilin-1 regulates vascular endothelial growth factor-mediated endothelial permeability
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DOI：
10.1161/01.res.0000171756.13554.49
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发表时间：
2005-06-24
影响因子：
20.1
通讯作者：
Verin, AD
中科院分区：
文献类型：
--
作者：
Becker, PM;Waltenberger, J;Verin, AD
神经纤毛蛋白-1（Npn-1）是一种结合血管内皮生长因子（VEGF）的细胞表面受体，VEGF是内皮渗透性、趋化性和增殖的有效介质。在体外，Npn-1可与VEGF受体2（VEGFR 2）复合，增强VEGFR 2介导的内皮细胞趋化和增殖。为了确定Npn-1/VEGFR 2复合物在VEGF诱导的内皮屏障功能障碍中的作用，用单独的Npn 1或VEGFR 2（分别为PAE/Npn和PAE/KDR）或VEGFR 2和Npn-1（PAE/KDR/Npn-1）稳定转染内皮细胞。通过测量跨内皮电阻（TER）估计的PAE/Npn和PAE/KDR细胞系的渗透性未被VEGF改变（165）。相比之下，PAE/KDR/Npn-1细胞的TER在VEGF（165）（10至200 ng/mL）后以剂量依赖性方式降低。在PAE/KDR/Npn-1中，VEGFR 2和2个下游信号中间体（p38和ERK 1/2 MAPK）参与VEGF介导的渗透性的激活也增加。与这些数据一致，抑制Npn-1而不是VEGFR 2减弱了VEGF（165）介导的人肺动脉内皮细胞（HPAE）的通透性，并且VEGF（121）（其不能连接Npn-1）不改变HPAE的TER。在诱导型肺特异性VEGF转基因小鼠中，Npn-1抑制还减弱了VEGF（165）介导的肺血管渗漏和VEGFR 2、p38和ERK 1/2 MAPK的激活。这些数据支持Npn-1在调节内皮屏障功能障碍中响应于VEGF的关键作用，并表明不同受体复合物的激活可能决定细胞对VEGF的反应的特异性。
Neuropilin-1 (Npn-1) is a cell surface receptor that binds vascular endothelial growth factor ( VEGF), a potent mediator of endothelial permeability, chemotaxis, and proliferation. In vitro, Npn-1 can complex with VEGF receptor-2 (VEGFR2) to enhance VEGFR2-mediated endothelial cell chemotaxis and proliferation. To determine the role of Npn-1/VEGFR2 complexes in VEGF-induced endothelial barrier dysfunction, endothelial cells were stably transfected with Npn1 or VEGFR2 alone (PAE/Npn and PAE/KDR, respectively), or VEGFR2 and Npn-1 (PAE/KDR/Npn-1). Permeability, estimated by measurement of transendothelial electrical resistance (TER), of PAE/Npn and PAE/KDR cell lines was not altered by VEGF(165). In contrast, TER of PAE/KDR/Npn-1 cells decreased in dose-dependent fashion following VEGF(165) (10 to 200 ng/mL). Activation of VEGFR2, and 2 downstream signaling intermediates (p38 and ERK1/2 MAPK) involved in VEGF-mediated permeability, also increased in PAE/KDR/Npn-1. Consistent with these data, inhibition of Npn-1, but not VEGFR2, attenuated VEGF(165)-mediated permeability of human pulmonary artery endothelial cells (HPAE), and VEGF(121) (which cannot ligate Npn-1) did not alter TER of HPAE. Npn-1 inhibition also attenuated both VEGF(165)-mediated pulmonary vascular leak and activation of VEGFR2, p38, and ERK1/2 MAPK, in inducible lung-specific VEGF transgenic mice. These data support a critical role for Npn-1 in regulating endothelial barrier dysfunction in response to VEGF and suggest that activation of distinct receptor complexes may determine specificity of cellular response to VEGF.