十字路口的连接：机械提示对内皮细胞 - 细胞连接构象和血管通透性的影响
Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability
影响因子:4.70000
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
摘要
细胞依赖于脉管系统中精确调节屏障功能，以维持生理稳定性并促进必需物质的运输。内皮细胞通过专门的粘附剂和紧密的连接蛋白复合物来实现这一目标，该蛋白质复合物控制了跨血管床的细胞细胞渗透性。由血管内皮（VE） - 钙粘着蛋白和相关蛋白链蛋白锚定为肌动蛋白细胞骨架的粘附连接，介导均电粘附对于屏障完整性至关重要。相比之下，由闭合蛋白，claudin和连接粘附分子A组成的紧密连接与Zonula occludens蛋白相互作用，增强了对屏障选择性必不可少的细胞间连接。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，受局部生化和机械提示调节。这些结构适应在诸如慢性炎症之类的疾病情况下起着关键作用，在慢性炎症中，连接重塑有助于在从癌症到心血管疾病的情况下观察到的血管通透性提高。相反，由于其独特的分子组成和紧密的组织，大脑微脉管系统的专业连接装置对治疗药物的递送构成了挑战。该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渗透性的影响。通过强调量化连接变化的最新进展和理解机械转导途径，我们阐明了细胞接触和血流动力学流动的物理力如何影响连接动力学。
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.