Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia 23284.
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213.
Mol Biol Cell. 2022 Sep 15;33(11):ar101. doi: 10.1091/mbc.E22-02-0064. Epub 2022 Jul 27.
Vascular endothelial cells (ECs) have been shown to be mechanoresponsive to the forces of blood flow, including fluid shear stress (FSS), the frictional force of blood on the vessel wall. Recent reports have shown that FSS induces epigenetic changes in chromatin. Epigenetic changes, such as methylation and acetylation of histones, not only affect gene expression but also affect chromatin condensation, which can alter nuclear stiffness. Thus, we hypothesized that changes in chromatin condensation may be an important component for how ECs adapt to FSS. Using both in vitro and in vivo models of EC adaptation to FSS, we observed an increase in histone acetylation and a decrease in histone methylation in ECs adapted to flow as compared with static. Using small molecule drugs, as well as vascular endothelial growth factor, to change chromatin condensation, we show that decreasing chromatin condensation enables cells to more quickly align to FSS, whereas increasing chromatin condensation inhibited alignment. Additionally, we show data that changes in chromatin condensation can also prevent or increase DNA damage, as measured by phosphorylation of γH2AX. Taken together, these results indicate that chromatin condensation, and potentially by extension nuclear stiffness, is an important aspect of EC adaptation to FSS.
血管内皮细胞（ECs）对血流的力，包括流体切应力（FSS），即血液对血管壁的摩擦力，具有机械反应性。最近的报告表明，FSS 会引起染色质的表观遗传变化。表观遗传变化，如组蛋白的甲基化和乙酰化，不仅会影响基因表达，还会影响染色质的凝聚，从而改变核硬度。因此，我们假设染色质凝聚的变化可能是 EC 适应 FSS 的重要组成部分。通过体外和体内 EC 适应 FSS 的模型，我们观察到与静态相比，适应流动的 EC 中的组蛋白乙酰化增加，组蛋白甲基化减少。我们使用小分子药物以及血管内皮生长因子来改变染色质凝聚，结果表明，降低染色质凝聚可使细胞更快地适应 FSS，而增加染色质凝聚则抑制了细胞的适应。此外，我们还展示了数据，表明染色质凝聚的变化也可以预防或增加 DNA 损伤，如γH2AX 的磷酸化所测量的。总之，这些结果表明，染色质凝聚，以及可能的核硬度，是 EC 适应 FSS 的一个重要方面。
