Department of Pulmonology, Amsterdam University Medical Center, the Netherlands (J.A.).
Department of Medical Oncology, Amsterdam University Medical Center, the NetherlandsInstitute of Biology, Leiden University, the Netherlands (C.M.).
Circ Res. 2023 Feb 3;132(3):355-378. doi: 10.1161/CIRCRESAHA.122.322332. Epub 2023 Feb 2.
The endothelium is a dynamic, semipermeable layer lining all blood vessels, regulating blood vessel formation and barrier function. Proper composition and function of the endothelial barrier are required for fluid homeostasis, and clinical conditions characterized by barrier disruption are associated with severe morbidity and high mortality rates. Endothelial barrier properties are regulated by cell-cell junctions and intracellular signaling pathways governing the cytoskeleton, but recent insights indicate an increasingly important role for integrin-mediated cell-matrix adhesion and signaling in endothelial barrier regulation. Here, we discuss diseases characterized by endothelial barrier disruption, and provide an overview of the composition of endothelial cell-matrix adhesion complexes and associated signaling pathways, their crosstalk with cell-cell junctions, and with other receptors. We further present recent insights into the role of cell-matrix adhesions in the developing and mature/adult endothelium of various vascular beds, and discuss how the dynamic regulation and turnover of cell-matrix adhesions regulates endothelial barrier function in (patho)physiological conditions like angiogenesis, inflammation and in response to hemodynamic stress. Finally, as clinical conditions associated with vascular leak still lack direct treatment, we focus on how understanding of endothelial cell-matrix adhesion may provide novel targets for treatment, and discuss current translational challenges and future perspectives.
内皮是一层动态的、半透性的细胞层，覆盖着所有的血管，调节着血管的形成和屏障功能。适当的内皮屏障组成和功能对于液体平衡是必需的，而以屏障破坏为特征的临床状况与严重的发病率和高死亡率相关。内皮屏障特性受细胞间连接和细胞骨架调节的细胞内信号通路调节，但最近的研究结果表明，整合素介导的细胞-基质黏附及其相关信号通路在调节内皮屏障方面起着越来越重要的作用。在这里，我们讨论了以内皮屏障破坏为特征的疾病，并概述了内皮细胞-基质黏附复合物的组成及其相关信号通路、它们与细胞-细胞连接的串扰以及与其他受体的串扰。我们进一步介绍了细胞-基质黏附在各种血管床的发育和成熟/成年内皮中的作用的最新见解，并讨论了细胞-基质黏附的动态调节和周转如何在血管生成、炎症和对血流动力学应激等（病理）生理条件下调节内皮屏障功能。最后，由于与血管渗漏相关的临床状况仍然缺乏直接的治疗方法，我们专注于对内皮细胞-基质黏附的理解如何为治疗提供新的靶点，并讨论当前的转化挑战和未来的前景。
