TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation
TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation
复制标题
TNFSF15 通过诱导 VEGFR2 去磷酸化来抑制 VEGF 刺激的血管通透性过高。
DOI：
10.1096/fj.201600800r
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Li, Lu-Yuan
中科院分区：
文献类型：
--
作者：
Yang, Gui-Li;Zhao, Zilong;Li, Lu-Yuan
血管通透性过高在包括中风和心肌梗塞在内的缺血性疾病以及炎症和癌症中是至关重要的。众所周知，VEGF-VEGFR 2信号通路在促进血管通透性方面是关键的;然而，限制血管通透性以维持血管完整性的平衡机制尚未完全理解。我们报告，TNF超家族成员15（TNFSF 15），主要由血管内皮细胞和这些相同的细胞的增殖的特异性抑制剂产生的细胞因子，可以抑制VEGF诱导的血管通透性在体外和体内，和死亡受体3（DR 3），TNFSF 15的细胞表面受体，介导TNFSF 15诱导的VEGFR 2的去磷酸化。含Src同源区2结构域的磷酸酶-1（SHP-1）在TNFSF 15与DR 3相互作用后与DR 3结合。此外，由VEGFR 2、DR 3和SHP-1组成的蛋白质复合物响应于TNFSF 15和VEGF对内皮细胞的作用而形成。这似乎是合理的，这种蛋白质复合物提供了TNFSF 15诱导抑制VEGF刺激的血管通透性过高的分子机制的结构基础。杨，G- L.，赵志，秦，T.- T.，Wang，D.，Chen，L.，中国地质大学，Xiang，R.，Xi，Z.，江，R.张志-美国，张杰，李L- Y. TNFSF 15通过诱导VEGFR 2去磷酸化抑制VEGF刺激的血管通透性过高。
Vascular hyperpermeability is critical in ischemic diseases, including stroke and myocardial infarction, as well as in inflammation and cancer. It is well known that the VEGF-VEGFR2 signaling pathways are pivotal in promoting vascular permeability; however, counterbalancing mechanisms that restrict vascular permeability to maintain the integrity of blood vessels are not yet fully understood. We report that TNF superfamily member 15 (TNFSF15), a cytokine largely produced by vascular endothelial cells and a specific inhibitor of the proliferation of these same cells, can inhibit VEGF-induced vascular permeability in vitro and in vivo, and that death receptor 3 (DR3), a cell surface receptor of TNFSF15, mediates TNFSF15-induced dephosphorylation of VEGFR2. Src homology region 2 domain-containing phosphatase-1 (SHP-1) becomes associated with DR3 upon TNFSF15 interaction with the latter. In addition, a protein complex consisting of VEGFR2, DR3, and SHP-1 is formed in response to the effects of TNFSF15 and VEGF on endothelial cells. It is plausible that this protein complex provides a structural basis for the molecular mechanism in which TNFSF15 induces the inhibition of VEGF-stimulated vascular hyperpermeability.-Yang, G.-L., Zhao, Z., Qin, T.-T., Wang, D., Chen, L., Xiang, R., Xi, Z., Jiang, R., Zhang, Z.-S., Zhang, J., Li. L.-Y. TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation.