Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells
Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells
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DOI：
10.1152/ajpheart.2001.281.1.h22
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发表时间：
2001-07-01
影响因子：
4.8
通讯作者：
Frangos, JA
中科院分区：
文献类型：
--
作者：
Bao, XP;Lu, CY;Frangos, JA
本研究旨在探讨剪切力(TGS)诱导内皮细胞增殖的细胞内信号转导途径，重点研究细胞外信号调节激酶1和2(ERK1/2)的作用。利用明确的脉冲流、脉冲流、阶跃流和斜坡层流图，我们发现TGS(脉冲流和脉冲流)诱导ERK1/2的磷酸化增强并持续(30min)高于阶梯流(先是剪切阶跃增加然后是稳定剪切)，而单独的稳定剪切(斜坡流)下调ERK1/2的激活。一氧化氮(NO)既介导了TGS的刺激作用，也介导了稳定剪切对内皮细胞ERK1/2磷酸化的抑制作用。活性氧物种(ROS)也被证明与TGS诱导的ERK1/2磷酸化有关。G(Q/11)和G(I3)都是TGS激活ERK1/2所必需的。最后，通过抑制ERK1/2，TGS诱导的内皮细胞增殖反应被取消。我们的研究证实了G蛋白、NO和ROS在TGS依赖的ERK1/2激活和血管内皮细胞增殖反应中起重要作用。
The aim of the current study was to investigate the intracellular signaling cascade that leads to temporal gradients in shear (TGS) induced endothelial cell proliferation, with a focus on the involvement of extracellular signal-regulated kinases 1 and 2 (ERK1/2). With the use of well-defined pulsatile, impulse, step, and ramp laminar flow profiles, we found that TGS (impulse flow and pulsatile flow) induced an enhanced and sustained (>30 min) phosphorylation of ERK1/2 relative to step flow (which contains a step increase in shear followed by steady shear), whereas steady shear (ramp flow) alone downregulated activated ERK1/2. Nitric oxide (NO) was found to mediate both the stimulatory effect of TGS and the inhibitory effect of steady shear on endothelial ERK1/2 phosphorylation. Reactive oxygen species (ROS) were also demonstrated to be associated with TGS-induced ERK1/2 phosphorylation. Both G(q/11) and G(i3) were necessary for the activation of ERK1/2 by TGS. Finally, the TGS-induced endothelial proliferative response was abolished by ERK1/2 inhibition. Our study demonstrated the essential role of G proteins, NO, and ROS in TGS-dependent ERK1/2 activation and proliferative response in vascular endothelial cells.