FLUID SHEAR-STRESS INDUCES ENDOTHELIAL TRANSFORMING GROWTH-FACTOR-BETA-1 TRANSCRIPTION AND PRODUCTION - MODULATION BY POTASSIUM CHANNEL BLOCKADE
FLUID SHEAR-STRESS INDUCES ENDOTHELIAL TRANSFORMING GROWTH-FACTOR-BETA-1 TRANSCRIPTION AND PRODUCTION - MODULATION BY POTASSIUM CHANNEL BLOCKADE
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DOI：
10.1172/jci117787
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发表时间：
1995-03-01
影响因子：
15.9
通讯作者：
GIBBONS, GH
中科院分区：
文献类型：
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作者：
OHNO, M;COOKE, JP;GIBBONS, GH
内皮细胞具有响应血流动力学刺激而调节血管结构的能力。我们测试了这样的假设：内皮暴露于增加的层流剪切应力会通过 K+ 通道电流调节的信号转导途径诱导 TGF beta 1 的表达。尽管 TGF beta 1 通常以潜伏、非活性形式分泌，但将培养的内皮细胞暴露于稳定的层流剪切应力 (20 dynes/cm(2)) 会诱导生物活性 TGF beta 1 的产生增加。活性 TGF beta 1 的这种增加与刺激 2 小时内 TGF beta 1 mRNA 表达的持续增加有关。 TGF beta 1 mRNA 水平的增加与生理范围内剪切应力的强度成正比。剪切应力对 TGF β 1 mRNA 表达的影响在转录水平上受到调节，如核径流研究和 TGF β 1 启动子-报告基因构建体的瞬时转染所定义的。用四乙铵阻断内皮 K+ 通道可显着抑制： TGF beta 1 基因转录的激活；稳态 mRNA 水平增加；以及响应剪切应力而产生活性 TGF beta 1。这些数据表明内皮K+通道和自分泌-旁分泌TGFβ1可能参与介导血流诱导的血管重塑的机械传导机制。
The endothelium has the capacity to modulate vascular structure in response to hemodynamic stimuli. We tested the hypothesis that exposure of the endothelium to increased laminar shear stress induces the expression of TGF beta 1 via a signal transduction pathway modulated by K+ channel currents. Although TGF beta 1 is normally secreted in a latent, inactive form, exposure of cultured endothelial cells to steady laminar shear stress (20 dynes/cm(2)) induced increased generation of biologically active TGF beta 1. This increase in active TGF beta 1 was associated with a sustained increase in TGF beta 1 mRNA expression within 2 h of stimulation. TGF beta 1 mRNA levels increased in direct proportion to the intensity of the shear stress within the physiologic range. The effect of shear stress on TGF beta 1 mRNA expression was regulated at the transcriptional level as defined by nuclear run-off studies and transient transfection of a TGF beta 1 promoter-reporter gene construct. Blockade of endothelial K+ channels with tetraethylammonium significantly inhibited: activation of TGF beta 1 gene transcription; increase in steady state mRNA levels; and generation of active TGF beta 1 in response to shear stress. These data suggest that endothelial K+ channels and autocrine-paracrine TGF beta 1 may be involved in the mechanotransduction mechanisms mediating flow-induced vascular remodeling.