幸存者调节血管光滑肌细胞中的细胞内硬度和细胞外矩阵的产生

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Amanda Krajnik¹, Erik Nimmer², Joseph A Brazzo¹

¹Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.

APL bioengineering

|October 23, 2023

概括

幸存者通过控制血管光滑肌细胞 (VSMCs) 的细胞外基质 (ECM) 生产和细胞内硬度来调节动脉硬度. 这种蛋白质将机械张力与ECM合成联系起来,为心血管疾病治疗提供了一个新的目标.

科学领域:

心血管生物学心血管生物学
细胞机械传导细胞机械传导
生物材料科学生物材料科学

背景情况:

血管功能障碍,包括动脉样硬化和高血压,涉及动脉狭窄和硬化.
异常的血管光滑肌细胞 (VSMC) 增殖和细胞外基质 (ECM) 沉积有助于动脉狭窄.
将动脉硬与VSMC行为联系在一起的精确机制仍然不完全理解.

研究的目的:

研究Survivin在调节VSMC中硬度介导的ECM合成和细胞内硬度中的作用.
阐明连接机械线索到生存表达和功能的信号通路.

主要方法:

在动脉损伤的小鼠模型中进行全转录组分析.
在不同硬度的水凝上培养人体VSMC的体外细胞培养.
基因沉默和子宫外的生存表达.
原子力显微镜用于细胞内硬度测量.
药理上抑制Rac和Rho信号通路.
对FAK酸化的分析.

主要成果:

在受伤的动脉和在硬基板上培养的VSMC中,幸存者的表达是上调的.
抑制的幸存者减少了性诱导的ECM蛋白表达 (原-I,纤维素, lysyl氧化酶) 和细胞内性.
宫外幸存者表达在软基质上拯救了ECM蛋白水平,并增加了细胞内硬度.
抑制Rac和Rho通路减少了幸存者的表达,将细胞内紧张关系与幸存者的诱导联系起来.
抑制生存素降低了FAK酸化,这表明一个反循环.

结论:

幸存者是VSMC细胞内硬性和ECM产生的关键调节者,以响应机械线索.
一条新的途径将细胞内紧张 (通过Rac/Rho) 连接到生存诱导和随后的ECM合成.
幸存者信号传输,可能通过FAK,在维持动脉硬性方面发挥着至关重要的作用.
幸存者代表了由动脉硬化为特征的心血管疾病的潜在治疗标.

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