ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-03-25 Epub Date: 2025-02-19 DOI:10.1016/j.celrep.2025.115288

Surya Prakash Rao Batta, Marc Rio, Corentin Lebot, Céline Baron-Menguy, Maxence Bodet, Reda Moutaoukil, Robin Le Ruz, Ibtissam Babahnini, Gervaise Loirand, Anne-Clémence Vion

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Abstract

The shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity, and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. When phosphorylated, ARHGEF18 interacts with tight junctions; participates in EC elongation, alignment, and migration; and allows the maintenance of the endothelial barrier under physiological flow conditions. In mice, ARHGEF18 is involved in tight junction formation, flow response of ECs, and the control of vascular permeability. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeability in vivo.

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ARHGEF18是一种控制内皮紧密连接和血管渗漏的血流响应交换因子。

血流引起的剪切应力是内皮细胞（EC）生物学和形态学的主要调节因子。Rho蛋白介导的细胞骨架重塑是EC对血流反应的早期和必要步骤。然而，Rho蛋白信号如何受剪切应力控制仍不清楚。在这里，我们证明了ECs中Rho核苷酸交换因子（RhoGEF） ARHGEF18的磷酸化、活性和表达受到剪切应力大小的调节。当磷酸化时，ARHGEF18与紧密连接相互作用；参与EC延伸、对齐和迁移；并允许在生理流动条件下维持内皮屏障。在小鼠中，ARHGEF18参与紧密连接的形成、内皮细胞的流动反应和血管通透性的控制。总之，我们的研究结果确定了ARHGEF18是ec中第一个血流敏感的RhoGEF，其活性对于维持细胞间连接和体内血管通透性的控制至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.