A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability
A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability
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DOI：
10.1182/blood.v97.5.1321
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发表时间：
2001-03-01
期刊：
影响因子：
20.3
通讯作者：
Risau, W
中科院分区：
文献类型：
--
作者：
Clauss, M;Sunderkötter, C;Risau, W
血管内皮生长因子（VEGF）诱导血管生成和血管通透性增加，这两个过程被认为对肿瘤生长和将药物递送至肿瘤部位都很重要。这项研究表明，肿瘤坏死因子（tmTNF）的跨膜表达上调的小鼠甲基胆蒽（甲）诱导肉瘤的内皮细胞相比，相邻的正常真皮血管系统，也存在于培养的人内皮细胞。进一步表明，在体外和体内VEGF介导的内皮细胞通透性过高需要tmTNF。TNF的这种允许活性似乎是选择性的，因为抗TNF抗体消融了VEGF诱导的渗透性，但没有培养的人内皮细胞的增殖。此外，tnf基因缺陷的小鼠在血管形成方面没有明显缺陷，发育正常，但对VEGF给药没有反应，血管通透性增加。随后的研究表明，tmTNF和VEGF信号通路在第二信使“应激活化蛋白激酶-2”（SAPK-2）/p38的水平上相互作用：（1）在体外上调tmTNF的内皮表达导致SAPK-2/p38的持续激活;（2）在体内SAPK-2/p38激活的抑制剂消除VEGF的血管通透性活性。总之，该研究发现tmTNF的连续自分泌信号通过增加血管通透性使内皮细胞对VEGF敏感，从而为操纵血管通透性过高提供了新的治疗概念。（血。2001;97：1321-1329）（C）2001年由美国血液学会。
Vascular endothelial growth factor (VEGF) induces both angiogenesis and an increase in Vascular permeability, 2 processes that are considered to be important for both tumor growth and the delivery of drugs to the site of tumors. This study demonstrates that transmembrane expression of tumor necrosis factor (tmTNF) is up-regulated in the endothelium of a murine methylcholanthrene (meth A)-induced sarcoma in comparison to the adjacent normal dermal vasculature and is also present on cultivated human endothelial cells. It is further shown that tmTNF is required for VEGF-mediated endothelial hyperpermeability in vitro and in vivo. This permissive activity of TNF appears to be selective, because anti-TNF antibodies ablated the VEGF-induced permeability but not proliferation of cultivated human endothelial cells. Furthermore, tnf gene-deficient mice show no obvious defects in vascularization and develop normally but failed to respond to administration of VEGF with an increase in vascular permeability. Subsequent studies indicated that the tmTNF and VEGF signaling pathways con verge at the level of a secondary messenger, the "stress-activated protein kinase-2" (SAPK-2)/p38: (1) up-regulated endothelial expression of tmTNF resulted in the continuous activation of SAPK-2/p38 in vitro, and (2) an inhibitor of SAPK-2/p38 activation abolished the vascular permeability activity; of VEGF in vivo. In conclusion, the study's finding that continuous autocrine signaling by tmTNF sensitizes endothelial cells to respond to VEGF by increasing their vascular permeability provides new therapeutic concepts for manipulating vascular hyperpermeability. (Blood. 2001;97:1321-1329) (C) 2001 by The American Society of Hematology.