TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation.
TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation.
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DOI：
10.1038/srep14257
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发表时间：
2015-09-21
影响因子：
4.6
通讯作者：
Thodeti CK
中科院分区：
文献类型：
--
作者：
Thoppil RJ;Adapala RK;Cappelli HC;Kondeti V;Dudley AC;Gary Meszaros J;Paruchuri S;Thodeti CK
内皮细胞增殖是血管生成过程中的关键事件，受可溶性因子和机械力的调节。尽管肿瘤细胞的增殖被广泛研究，但对肿瘤内皮细胞(TEC)的增殖及其在肿瘤血管生成中的作用却知之甚少。我们最近发现，机械敏感离子通道TRPV4在TEC中的表达减少会导致异常的机械敏感性，从而导致异常的血管生成。在这里，我们表明，与正常内皮细胞(NEC)相比，TEC表现出更强的增殖能力。此外，我们发现TEC表现出高的基础ERK1/2磷酸化和在细胞周期的G1/S期重要的增殖基因的表达增加。重要的是，用小分子激活剂GSK1016790A(GSK)药理激活TRPV4可显著抑制TEC的增殖，但对NEC和肿瘤细胞(上皮)本身的增殖无明显影响。TRPV4激活对TEC增殖的抑制作用与高基础ERK1/2磷酸化水平的降低有关。最后，使用同基因肿瘤模型显示，在体内，加入GSK的TRPV4激活显著降低了内皮细胞的增殖。我们的研究结果表明，TRPV4通道通过选择性抑制肿瘤内皮细胞的增殖来调节肿瘤血管生成。
Endothelial cell proliferation is a critical event during angiogenesis, regulated by both soluble factors and mechanical forces. Although the proliferation of tumor cells is studied extensively, little is known about the proliferation of tumor endothelial cells (TEC) and its contribution to tumor angiogenesis. We have recently shown that reduced expression of the mechanosensitive ion channel TRPV4 in TEC causes aberrant mechanosensitivity that result in abnormal angiogenesis. Here, we show that TEC display increased proliferation compared to normal endothelial cells (NEC). Further, we found that TEC exhibit high basal ERK1/2 phosphorylation and increased expression of proliferative genes important in the G1/S phase of the cell cycle. Importantly, pharmacological activation of TRPV4, with a small molecular activator GSK1016790A (GSK), significantly inhibited TEC proliferation, but had no effect on the proliferation of NEC or the tumor cells (epithelial) themselves. This reduction in TEC proliferation by TRPV4 activation was correlated with a decrease in high basal ERK1/2 phosphorylation. Finally, using a syngeneic tumor model revealed that TRPV4 activation, with GSK, significantly reduced endothelial cell proliferation in vivo. Our findings suggest that TRPV4 channels regulate tumor angiogenesis by selectively inhibiting tumor endothelial cell proliferation.