Tianjin Neurological Institute, Key Laboratory of Head Trauma Clinics and Neuro-Regeneration, Ministry of Education and Tianjin Municipality, 300052 Tianjin, China.
2State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Collaborative Research Center for Biotherapy, Nankai University, Tianjin, 300071 China.
Signal Transduct Target Ther. 2018 Aug 10;3:21. doi: 10.1038/s41392-018-0023-8. eCollection 2018.
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 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.
血管通透性增加发生在血管生成和几种病理生理条件下，导致间质液压力升高和淋巴管生成。这些密切相关的事件是如何被调节的，这是一个关于维持血管内稳态和治疗疾病的基本问题，如癌症、中风和心肌梗死。血管内皮生长因子受体介导的信号，特别是 VEGFR-1、-2 和 -3，在促进血管和淋巴管生长中起着核心作用。这些信号通路被肿瘤坏死因子超家族 15（TNFSF15）诱导的信号所平衡或增强，在后一种情况下，VEGFR3 被增强。TNFSF15 可以同时下调膜结合的 VEGFR1 并上调可溶性 VEGFR1，从而将 VEGF/VEGFR1 信号从促血管生成转变为抗血管生成。此外，TNFSF15 抑制 VEGF 诱导的 VEGFR2 磷酸化，从而抑制 VEGFR2 介导的血管通透性增强。第三，也许更有趣的是，TNFSF15 能够刺激淋巴管内皮细胞中的基因表达，从而增强 VEGF-C/D-VEGFR3 促进的淋巴管生成。我们在这篇综述中讨论了 TNFSF15 和 VEGF 之间相互作用的关系。
