Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis
Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis
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DOI：
10.2353/ajpath.2006.060603
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发表时间：
2006-11-01
影响因子：
6
通讯作者：
Min, Wang
中科院分区：
文献类型：
--
作者：
Luo, Dianhong;Luo, Yan;Min, Wang
我们之前已经证明肿瘤坏死因子（TNF）通过其两个受体TNFR1和TNFR2在血管内皮细胞（ECs）中引发不同的信号通路。在这里，我们使用股动脉结扎模型来证明，与野生型小鼠相比，tnfr1敲除（KO）小鼠的临床恢复能力、肢体灌注能力和缺血储备能力增强，而TNFR2-KO小鼠则降低。同样，在TNFR1-KO小鼠中，上肢缺血引发的侧枝生长（动脉生成）和下肢毛细血管形成和血管成熟（血管生成）在TNFR1-KO小鼠中增强，而在TNFR2-KO小鼠中则减弱。此外，我们的研究结果表明，血管增生，而不是巨噬细胞和淋巴细胞的浸润，是TNFR1-KO和TNFR2-KO小鼠表型差异的原因。在野生型动物中，血管内皮中的TNFR2蛋白在缺血反应中高度上调，导致TNFR2特异性信号通路增加，这可以通过TNFR2- traf2复合物的形成和TNFR2特异性激酶Bmx/Etk的激活来确定。在离体小鼠内皮细胞中，TNFR2的激活诱导核因子κ b依赖性报告基因表达、内皮细胞存活和迁移。相反，激活TNFR1可抑制EC迁移和EC凋亡。这些数据表明，TNFR1和TNFR2在缺血介导的动脉生成和血管生成中发挥着不同的作用，部分原因是它们对EC存活和迁移的作用相反。
We have previously shown that tumor necrosis factor (TNF) acts via its two receptors TNFR1 and TNFR2 to elicit distinct signaling pathways in vascular endothelial cells (ECs). Here we used a femoral artery ligation model to demonstrate that TNFR1-knockout (KO) mice had enhanced, whereas TNFR2-KO had reduced, capacity in clinical recovery, limb perfusion, and ischemic reserve capacity compared with the wildtype mice. Consistently, ischemia-initiated collateral growth (arteriogenesis) in the upper limb and capillary formation and vessel maturation (angiogenesis) in the lower limb were enhanced in TNFR1-KO but were reduced in TNFR2-KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophages and lymphocytes, accounted for the phenotypic differences between the TNFR1-KO and TNFR2-KO mice. in wild-type animals TNFR2 protein in vascular endothelium was highly up-regulated in response to ischemia, leading to increased TNFR2-specific signaling as determined by the formation TNFR2-TRAF2 complex and activation of TNFR2-specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced nuclear factor-kappa B-dependent reporter gene expression, EC survival, and migration. In contrast, activation of TNFR1 caused inhibition of EC migration and EC apoptosis. These data demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis, partly because of their opposite effects on EC survival and migration.