{"title":"十字路口的连接:机械线索对内皮细胞-细胞连接构型和血管通透性的影响》(The Impact of Mechanical Cues on Endothelial Cell-Cell Junction Conformations and Vascular Permeability.","authors":"Ken D Brandon, William E Frank, Kimberly M Stroka","doi":"10.1152/ajpcell.00605.2023","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. 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引用次数: 0
摘要
细胞依靠精确调节血管内的屏障功能来维持生理稳定和促进重要物质的运输。内皮细胞通过特化的粘连蛋白和紧密连接蛋白复合物实现这一功能,这些复合物控制着血管床的细胞旁通透性。粘连接头由 VE-粘连蛋白和相关的 catenins 固定在肌动蛋白细胞骨架上,介导对屏障完整性至关重要的同亲粘附。与此相反,由闭塞素、凝集素和连接粘附分子 A 组成的紧密连接与闭塞斑块蛋白相互作用,加强了对屏障选择性至关重要的细胞间连接。内皮细胞-细胞连接在发育、成熟和重塑过程中表现出动态构象,并受局部生化和机械线索的调节。这些结构调整在慢性炎症等疾病中起着关键作用,从癌症到心血管疾病,连接重塑都会导致血管通透性增加。相反,脑微血管的特殊交界排列由于其独特的分子组成和严密的组织结构,给治疗药物的输送带来了挑战。这篇评论探讨了内皮细胞-细胞连接构象的分子机制及其对血管通透性的影响。通过重点介绍在量化连接变化和了解机械传导途径方面的最新进展,我们阐明了细胞接触和血液动力学流动所产生的物理力是如何影响连接动态的。
Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability.
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.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.