Tumor necrosis factor and vascular endothelial growth factor induce endothelial integrin repertories, regulating endovascular differentiation and apoptosis in a human extravillous trophoblast cell line
Tumor necrosis factor and vascular endothelial growth factor induce endothelial integrin repertories, regulating endovascular differentiation and apoptosis in a human extravillous trophoblast cell line
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DOI：
10.1095/biolreprod.104.039479
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发表时间：
2005-07-01
影响因子：
3.6
通讯作者：
Nakano, H
中科院分区：
文献类型：
--
作者：
Fukushima, K;Miyamoto, S;Nakano, H
血管生成对于人类发育至关重要。绒毛外滋养层（EVT）细胞在血管内分化过程中模拟血管生成中的内皮细胞，诱导螺旋动脉重塑，从而增加流向绒毛内空间的血流。我们之前已经证明，肿瘤坏死因子 (TNF) α 调节人 EVT 细胞系 TCL1 中参与细胞存活的 ITGA6 和 ITGA1 的表达。为了进一步研究血管内分化，我们检查了血管内皮生长因子（VEGF）、TNF和细胞外基质（ECM）对TCL1细胞的影响。接种在基质胶上的 TCL1 细胞显示出管状结构，特别让人想起内皮细胞的形态变化。抗ITGAV/ITGB3抗体显着减小了Matrigel上毛细血管网络的大小(P < 0.05)，并且还抑制了TCL1细胞中TNF诱导的细胞凋亡(P < 0.05)。 VEGF 诱导 ITGAV/ITGB3 亚基的表达和蛋白质聚集，就像 TNF 的情况一样，TNF 反过来又诱导 TCL1 细胞中 VEGF 的合成。可溶性 FLT1 抑制 TCL1 细胞中的这些活性，表明涉及 VEGF 轴的信号对于血管内分化至关重要。这些结果表明，在人类成功妊娠的建立和维持过程中，TNF、VEGF 和 ECM 通过整合素信号传导共同调节 EVT 行为，包括细胞存活和血管内分化。
Angiogenesis is crucial in human development. Extravillous trophoblast (EVT) cells mimic endothelial cells in angiogenesis during endovascular differentiation, inducing a remodeling of spiral arteries that increases blood flow toward the intravillous space. We have previously shown that tumor necrosis factor (TNF) alpha regulates expression of ITGA6 and ITGA1, which are involved in cell survival, in the human EVT cell line TCL1. To further investigate endovascular differentiation, we examined the effects of vascular endothelial growth factor (VEGF), TNF, and extracellular matrix (ECM) on TCL1 cells. Seeded on Matrigel, TCL1 cells show tube-like formation that specifically recalls morphological changes in endothelial cells. Anti-ITGAV/ITGB3 antibodies significantly reduced the size of the capillary network (P < 0.05) on Matrigel and also suppressed TNF-induced apoptosis (P < 0.05) in TCL1 cells. VEGF induced expression of ITGAV/ITGB3 subunits and protein aggregation, as in the case of TNF, which in turn, induces synthesis of VEGF in TCL1 cells. Soluble FLT1 suppressed these activities in TCL1 cells, indicating that signals involving VEGF axis are essential for endovascular differentiation. These results suggest that TNF, VEGF, and ECM collaboratively regulate EVT behavior, including cell survival and endovascular differentiation, through integrin signaling during establishment and maintenance of successful human pregnancies.