Sporkova Alexandra, Ghosh Subhajit, Al-Hasani Jaafar, Hecker Markus
Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research) Partner Site, Heidelberg/Mannheim, Germany.
Front Physiol. 2021 Nov 19;12:769321. doi: 10.3389/fphys.2021.769321. eCollection 2021.
Arterial hypertension is the leading risk factor for cardiovascular morbidity and mortality worldwide. However, little is known about the cellular mechanisms underlying it. In small arteries and arterioles, a chronic increase in blood pressure raises wall tension and hence stretches, namely, the medial vascular smooth muscle cells (VSMC) but also endothelial cell (EC) to cell contacts. Initially compensated by an increase in vascular tone, the continuous biomechanical strain causes a prominent change in gene expression in both cell types, frequently driving an arterial inward remodeling process that ultimately results in a reduction in lumen diameter, stiffening of the vessel wall, and fixation of blood pressure, namely, diastolic blood pressure, at the elevated level. Sensing and propagation of this supraphysiological stretch into the nucleus of VSMC and EC therefore seems to be a crucial step in the initiation and advancement of hypertension-induced arterial remodeling. Focal adhesions (FA) represent an important interface between the extracellular matrix and Lin11-Isl1-Mec3 (LIM) domain-containing proteins, which can translocate from the FA into the nucleus where they affect gene expression. The varying biomechanical cues to which vascular cells are exposed can thus be rapidly and specifically propagated to the nucleus. Zyxin was the first protein described with such mechanotransducing properties. It comprises 3 C-terminal LIM domains, a leucine-rich nuclear export signal, and N-terminal features that support its association with the actin cytoskeleton. In the cytoplasm, zyxin promotes actin assembly and organization as well as cell motility. In EC, zyxin acts as a transcription factor, whereas in VSMC, it has a less direct effect on mechanosensitive gene expression. In terms of homology and structural features, lipoma preferred partner is the nearest relative of zyxin among the LIM domain proteins. It is almost exclusively expressed by smooth muscle cells in the adult, resides like zyxin at FA but seems to affect mechanosensitive gene expression indirectly, possibly altering cortical actin dynamics. Here, we highlight what is currently known about the role of these LIM domain proteins in mechanosensing and transduction in vascular cells.
动脉高血压是全球心血管疾病发病和死亡的主要危险因素。然而，其潜在的细胞机制却鲜为人知。在小动脉和微动脉中，血压的长期升高会增加血管壁张力，从而使血管壁伸展，即中膜血管平滑肌细胞（VSMC）以及内皮细胞（EC）都会受到拉伸，进而影响细胞间的接触。最初，血管张力的增加可对此起到代偿作用，但持续的生物力学应变会导致这两种细胞类型的基因表达发生显著变化，常常引发动脉内向重塑过程，最终导致管腔直径减小、血管壁僵硬，并使血压（即舒张压）维持在升高水平。因此，这种超生理拉伸在VSMC和EC细胞核中的感知与传导似乎是高血压诱导的动脉重塑起始和进展过程中的关键步骤。黏着斑（FA）代表细胞外基质与含Lin11-Isl1-Mec3（LIM）结构域蛋白之间的重要界面，这些蛋白可从FA转位至细胞核，在细胞核中影响基因表达。因此，血管细胞所暴露的不同生物力学信号能够迅速且特异地传导至细胞核。桩蛋白是首个被描述具有这种机械转导特性的蛋白质。它包含3个C端LIM结构域、一个富含亮氨酸的核输出信号以及支持其与肌动蛋白细胞骨架结合的N端结构。在细胞质中，桩蛋白可促进肌动蛋白的组装、组织以及细胞运动。在EC中，桩蛋白作为转录因子发挥作用，而在VSMC中，它对机械敏感基因表达的影响则较为间接。就同源性和结构特征而言，脂肪瘤优先伴侣蛋白是LIM结构域蛋白中与桩蛋白亲缘关系最近的。它在成体中几乎仅由平滑肌细胞表达，与桩蛋白一样定位于FA，但似乎间接影响机械敏感基因表达，可能改变皮质肌动蛋白动力学。在此，我们重点介绍目前已知的这些LIM结构域蛋白在血管细胞机械感知和转导中的作用。
