Src/RUNX2参与调控周期性高张应变诱导的血管平滑肌细胞迁移
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1.上海交通大学 生命科学技术学院;2.上海市交通大学附属第六人民医院

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Src/RUNX2 Modulates the Migration of Vascular Smooth Muscle Cells Induced by Cyclic Stretch
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    摘要:

    目的 探讨周期性高张应变对血管平滑肌细胞(vascular smooth muscle cells, VSMCs)Src/Runt相关转录因子2(Runt related transcription factor 2,RUNX2)的影响,及其在VSMCs迁移过程中的调控作用。方法 应用FX-5000T张应变加载系统,对VSMCs施加幅度为5%(模拟生理条件)和15%(模拟高血压病理条件)的张应变;Western Blotting检测VSMCs内RUNX2和磷酸化Src表达量;IPA生物信息学分析Src对RUNX2的调控作用;小干扰RNA(small interfering RNA, siRNA)转染下调VSMCs中RUNX2表达,Src抑制剂-1抑制细胞内Src激酶活性;利用划痕愈合实验检测VSMCs的迁移能力。结果 15%高张应变显著增强VSMCs内RUNX2的表达水平;静态和15%张应变加载条件下,降低RUNX2的表达均显著抑制了VSMCs的迁移。IPA结果提示Src激酶可能通过多种分子调控RUNX2,且抑制Src活性后RUNX2的表达量显著降低;在施加15%高周期性张应变的同时抑制Src活性,高张应变诱导的RUNX2表达与VSMCs迁移被逆转。结论 高张应变上调Src激酶磷酸化促进RUNX2的表达,进而诱导VSMCs异常迁移。探讨张应变力学刺激调控VSMCs迁移的力学生物学分子机制,对于揭示血管生理稳态维持和血管病理重建的分子机制具有一定意义,并为寻找高血压血管重建临床诊断、治疗的转化研究提供了新视角。

    Abstract:

    Objective To investigate the effect of cyclic stretch on Src and Runx related transcription factor 2 (Runx2), and their pivotal roles in migration of vascular smooth muscle cells (VSMCs). Methods Cyclic stretch of 5% (simulated normotensive physiological condition) or 15% (simulated hypertensive pathological condition) amplitude was applied to VSMCs by FX-5000T system; wWestern Blotting was used to detect the expression of RUNX2 and phosphorylation of Src in VSMCs; IPA bioinformatic software was used to analyze the potential regulatory effect of Src on RUNX2; small interfering RNA (siRNA) was transfected to decrease the expression of RUNX2; Src inhibitor-1was used to repressed Src kinase activity; wound-healing assay was applied to detect VSMC migration. Results Compared with 5% cyclic stretch, 15% cyclic stretch significantly increased RUNX2 expression in VSMCs. Under both static and 15%-cyclic-stretch conditions, VSMC migration was significantly inhibited after reducing RUNX2 expression with siRNA transfection. IPA indicated that Src kinase may be the upstream modulator of RUNX2, and western blotting validated that RUNX2 expression was significantly decreased after inhibiting Src. Furthermore, under 15% cyclic stretch condition, Src inhibitor-1 markedly repressed RUNX2 expression and VSMC migration. Conclusion High cyclic stretch increased phosphorylation of Src kinase and expression of RUNX2, which subsequently induced VSMC abnormal migration. Exploring the mechanobiological mechanism of VSMC migration regulated by cyclic stretch may contribute to further revealing the mechanism of vascular physiological homeostasis and vascular pathological remodeling. In addition, it also may provide new perspective for the translational research of vascular remodeling upon hypertension.

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  • 收稿日期:2021-04-22
  • 最后修改日期:2021-05-31
  • 录用日期:2021-06-02
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