Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Mechanical Engineering, College of Engineering, Nihon University, Koriyama, Japan.
Am J Physiol Cell Physiol. 2023 Dec 1;325(6):C1532-C1544. doi: 10.1152/ajpcell.00393.2023. Epub 2023 Nov 6.
Endothelial cells (ECs) experience two different blood flow patterns: laminar and disturbed flow. Their responses to laminar flow contribute to vascular homeostasis, whereas their responses to disturbed flow result in EC dysfunction and vascular diseases. However, it remains unclear how ECs differentially sense laminar and disturbed flow and trigger signaling that elicits different responses. Here, we showed that ECs differentially sense laminar and disturbed flows by altering the lipid order of their plasma and mitochondrial membranes in opposite directions. This results in distinct changes in mitochondrial function, namely, increased adenosine triphosphate (ATP) production for laminar flow and increased hydrogen peroxide (HO) release for disturbed flow, leading to ATP- and HO-mediated signaling, respectively. When cultured human aortic ECs were subjected to laminar or disturbed flow in flow-loading devices, the lipid order of their plasma membranes immediately decreased in response to laminar flow and increased in response to disturbed flow. Laminar flow also decreased the lipid order of mitochondrial membranes and increased mitochondrial ATP production. In contrast, disturbed flow increased the lipid order of mitochondrial membranes and increased the release of HO from the mitochondria. The addition of cholesterol to the cells increased the lipid order of both membranes and abrogated laminar flow-induced ATP production, while treatment of the cells with a cholesterol-depleting reagent, methyl-β cyclodextrin, decreased the lipid order of both membranes and abolished disturbed flow-induced HO release, indicating that changes in the membrane lipid order and/or cholesterol content are closely linked to flow-induced changes in mitochondrial functions. How vascular endothelial cells (ECs) differentially sense laminar and disturbed flows and trigger intracellular signaling remains unclear. Here, we show that EC plasma membranes act as mechanosensors to discriminate between laminar and disturbed flows by undergoing opposite changes in their lipid order. Similar lipid order changes occur simultaneously in the mitochondrial membranes, which are linked to changes in mitochondrial function, that is, increased ATP production for laminar flow and increased HO release for disturbed flow.
内皮细胞（EC）经历两种不同的血流模式：层流和紊乱流。它们对层流的反应有助于血管稳态，而对紊乱流的反应则导致 EC 功能障碍和血管疾病。然而，目前尚不清楚 EC 如何区分层流和紊乱流并触发引发不同反应的信号。在这里，我们表明，EC 通过改变其质膜和线粒体膜的脂质有序性来区分层流和紊乱流，其方向相反。这导致线粒体功能的明显变化，即层流时增加三磷酸腺苷（ATP）的产生，紊乱流时增加过氧化氢（HO）的释放，分别导致 ATP 和 HO 介导的信号转导。当培养的人主动脉 EC 在流加载装置中受到层流或紊乱流时，其质膜的脂质有序性立即响应层流而降低，响应紊乱流而增加。层流还降低了线粒体膜的脂质有序性并增加了线粒体 ATP 的产生。相比之下，紊乱流增加了线粒体膜的脂质有序性并增加了 HO 从线粒体的释放。向细胞中添加胆固醇会增加两个膜的脂质有序性并阻断层流诱导的 ATP 产生，而用胆固醇耗竭试剂甲基-β环糊精处理细胞会降低两个膜的脂质有序性并消除紊乱流诱导的 HO 释放，表明膜脂质有序性和/或胆固醇含量的变化与线粒体功能的流动诱导变化密切相关。血管内皮细胞（EC）如何区分层流和紊乱流并触发细胞内信号仍不清楚。在这里，我们表明 EC 质膜通过经历脂质有序性的相反变化来作为机械感受器来区分层流和紊乱流。类似的脂质有序性变化同时发生在线粒体膜中，这与线粒体功能的变化有关，即层流时增加 ATP 的产生，紊乱流时增加 HO 的释放。
