交叉路口的连接：机械信号对内皮细胞-细胞连接构象及血管通透性的影响
Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability
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影响因子:4.7
分区:生物学3区 / 细胞生物学3区 生理学3区
发表日期:2024 Oct 01
作者:
Ken D Brandon, William E Frank, Kimberly M Stroka
DOI:
10.1152/ajpcell.00605.2023
摘要
血管内的屏障功能由内皮细胞通过特化的粘附连接和紧密连接蛋白复合物精确调控，以维持生理稳定性并促进重要物质的运输。内皮细胞通过由血管内皮（VE）钙粘蛋白及相关钙粘蛋白与肌动蛋白骨架连接的粘附连接，介导同源粘附，维护屏障完整性。而由封闭素、claudin和连接粘附分子A组成的紧密连接蛋白则与Zonula Occludens蛋白相互作用，增强细胞间连接，确保屏障选择性。在发育、成熟和重塑过程中，内皮细胞-细胞连接表现出动态构象变化，这些变化由局部的生化和机械信号调控。这些结构适应在慢性炎症等疾病背景中起到关键作用，例如连接重塑导致的血管通透性增加，从癌症到心血管疾病。相反，脑微血管的特殊连接结构因其独特的分子组成和紧密组织，对药物递送提出挑战。本文探讨了内皮细胞-细胞连接构象的分子机制及其对血管通透性的影响。通过强调近年来在定量连接变化和机械信号转导途径方面的研究进展，阐明了细胞接触和血流动力学等物理力如何影响连接动态。
Abstract
Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.