Counterbalance: modulation of VEGF/VEGFR activities by TNFSF15.
Counterbalance: modulation of VEGF/VEGFR activities by TNFSF15.
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平衡：TNFSF15 调节 VEGF/VEGFR 活性。
DOI：
10.1038/s41392-018-0023-8
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发表时间：
2018
影响因子：
39.3
通讯作者：
Li LY
中科院分区：
文献类型：
--
作者：
Yang GL;Li LY
血管通透性过高发生在血管生成和几种病理生物学条件下，产生升高的间质液压力和淋巴管生成。如何调节这些密切相关的事件是关于维持血管稳态和治疗疾病状况（诸如癌症、中风和心肌梗死）的根本重要问题。由血管内皮生长因子受体介导的信号，特别是VEGFR-1，-2和-3，主要参与促进血管和淋巴管生长。这些信号传导途径被肿瘤坏死因子超家族-15（TNFSF 15）诱导的信号抵消，或者在VEGFR 3的情况下被肿瘤坏死因子超家族-15（TNFSF 15）诱导的信号增强。TNFSF 15可以同时下调膜结合的VEGFR 1和上调可溶性VEGFR 1，从而将VEGF/VEGFR 1信号从促血管生成改变为抗血管生成。此外，TNFSF 15抑制VEGF诱导的VEGFR 2磷酸化，从而抑制VEGFR 2介导的血管通透性增强。第三，也许更有趣的是，TNFSF 15能够刺激淋巴管内皮细胞中的VEGFR 3基因表达，从而增强VEGF-C/D-VEGFR 3促进的淋巴管生成。本文就TNFSF 15与VEGF的相互作用关系进行综述。肿瘤坏死因子超家族15（TNFSF 15）蛋白平衡血管内皮生长因子（VEGF）的作用的能力突出了用于治疗破坏循环系统的疾病的新的治疗策略。天津神经病学研究所的杨桂丽和南开大学的李路元描述了TNFSF 15抑制VEGF受体1（VEGFR 1）介导的血管生长并抵消VEGFR 2介导的血管通透性增加的机制。有趣的是，TNFSF 15通过促进淋巴管内皮细胞中VEGFR 3基因表达来增强VEGFR 3对淋巴管形成的作用。进一步的研究将确定TNFSF 15调节血管和淋巴管特性的独特能力是否可以用来改善癌症，中风，心肌梗死和淋巴水肿等疾病的治疗。
Vascular hyperpermeability occurs in angiogenesis and several pathobiological conditions, producing elevated interstitial fluid pressure and lymphangiogenesis. How these closely related events are modulated is a fundamentally important question regarding the maintenance of vascular homeostasis and treatment of disease conditions such as cancer, stroke, and myocardial infarction. Signals mediated by vascular endothelial growth factor receptors, noticeably VEGFR-1, −2, and −3, are centrally involved in the promotion of both blood vessel and lymphatic vessel growth. These signaling pathways are counterbalanced or, in the case of VEGFR3, augmented by signals induced by tumor necrosis factor superfamily-15 (TNFSF15). TNFSF15 can simultaneously downregulate membrane-bound VEGFR1 and upregulate soluble VEGFR1, thus changing VEGF/VEGFR1 signals from pro-angiogenic to anti-angiogenic. In addition, TNFSF15 inhibits VEGF-induced VEGFR2 phosphorylation, thereby curbing VEGFR2-mediated enhancement of vascular permeability. Third, and perhaps more interestingly, TNFSF15 is capable of stimulating VEGFR3 gene expression in lymphatic endothelial cells, thus augmenting VEGF-C/D-VEGFR3-facilitated lymphangiogenesis. We discuss the intertwining relationship between the actions of TNFSF15 and VEGF in this review. The ability of tumor necrosis factor superfamily-15 (TNFSF15) protein to balance the actions of vascular endothelial growth factors (VEGFs) highlights new therapeutic strategies for the treatment of diseases that disrupt the circulatory system. Gui-Li Yang at the Tianjin Neurological Institute and Lu-Yuan Li at Nankai University describe the mechanisms through which TNFSF15 inhibits blood vessel growth mediated by VEGF receptor-1 (VEGFR1) and counterbalances the increase in vascular permeability mediated by VEGFR2. Interestingly, TNFSF15 enhances the effects of VEGFR3 on the formation of lymphatic vessels by promoting VEGFR3 gene expression in lymphatic endothelial cells. Further research will determine whether TNFSF15′s unique capacity to regulate the properties of both blood and lymph vessels can be harnessed to improve the treatment of conditions such as cancer, stroke, myocardial infarction and lymphoedema.
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