A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF receptor-2 activation retains the ability to induce vascular permeability
A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF receptor-2 activation retains the ability to induce vascular permeability
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DOI：
10.1074/jbc.274.49.34884
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发表时间：
1999-12-03
影响因子：
4.8
通讯作者：
Wilks, AF
中科院分区：
文献类型：
--
作者：
Stacker, SA;Vitali, A;Wilks, AF
血管内皮生长因子（VEGF）是发育和病理条件下血管发生和血管生成的主要介质。VEGF对血管内皮具有多种作用，包括刺激内皮细胞有丝分裂的能力和有效诱导血管通透性。这些活性至少部分是通过与两种高亲和力受体VEGFR-1和VEGFR-2的结合来介导的。在本研究中，我们对小鼠VEGF进行了突变，以确定VEGFR-2介导的功能所需的区域。开发了一种生物测定法，该生物测定法仅对VEGFR-2交联产生的信号有反应，从而可以评估这些突变体激活VEGFR-2的能力，一种突变体（VEGF 0），其VEGF的氨基酸83-89被相关胎盘生长因子的类似区域取代，与野生型VEGF相比，显示出显著降低的VEGFR-2结合，表明该区域是VEGF-VEGFR-2相互作用所需的。有趣的是，当在Miles测定中评价该突变体诱导血管通透性的能力时，与野生型VEGF相比，没有发现差异。此外，我们已经表明，结构相关的生长因子VEGF-D的VEGF同源结构域能够结合并激活VEGFR-2，但没有血管渗透活性，表明VEGFR-2结合与所有VEGF家族成员的渗透活性无关;这些数据表明VEGF介导的有丝分裂和血管通透性的不同机制，并提出了一种替代受体介导血管通透性的可能性。
Vascular endothelial growth factor (VEGF) is a major mediator of vasculogenesis and angiogenesis both during development and in pathological conditions. VEGF has a variety of effects on vascular endothelium, including the ability to stimulate endothelial cell mitogenesis, and the potent induction of vascular permeability. These activities are at least in part mediated by binding to two high affinity receptors, VEGFR-1 and VEGFR-2, In this study we have made mutations of mouse VEGF in order to define the regions that are required for VEGFR-2-mediated functions, Development of a bioassay, which responds only to signals generated by cross-linking of VEGFR-2, has allowed evaluation of these mutants for their ability to activate VEGFR-2, One mutant (VEGF0), which had amino acids 83-89 of VEGF substituted with the analogous region of the related placenta growth factor, demonstrated significantly reduced VEGFR-2 binding compared with wild type VEGF, indicating that this region was required for VEGF-VEGFR-2 interaction, Intriguingly, when this mutant was evaluated in a Miles assay for its ability to induce vascular permeability, no difference was found when compared with wild type VEGF, In addition we have shown that the VEGF homology domain of the structurally related growth factor VEGF-D is capable of binding to and activating VEGFR-2 but has no vascular permeability activity, indicating that VEGFR-2 binding does not correlate with permeability activity for all VEGF family members; These data suggest different mechanisms for VEGF-mediated mitogenesis and vascular permeability and raise the possibility of an alternative receptor mediating vascular permeability.