Purpose

The endothelial glycocalyx (GCX) plays a critical role in the health of the vascular system. Degradation of the GCX has been implicated in the onset of diseases like atherosclerosis and cancer because it disrupts endothelial cell (EC) function that is meant to protect from atherosclerosis and cancer. Examples of such EC function include interendothelial cell communication via gap junctions and receptor-mediated interactions between endothelial and tumor cells. This review focuses on GCX-dependent regulation of these intercellular interactions in healthy and diseased states. The ultimate goal is to build new knowledge that can be applied to developing GCX regeneration strategies that can control intercellular interaction in order to combat the progression of diseases such as atherosclerosis and cancer.

Methods

In vitro and in vivo studies were conducted to determine the baseline expression of GCX in physiologically relevant conditions. Chemical and mechanical GCX degradation approaches were employed to degrade the GCX. The impact of intact versus degraded GCX on intercellular interactions was assessed using cytochemistry, histochemistry, a Lucifer yellow dye transfer assay, and confocal, intravital, and scanning electron microscopy techniques.

Results

Relevant to atherosclerosis, we found that GCX stability determines the expression and functionality of Cx43 in gap junction-mediated EC-to-EC communication. Relevant to cancer metastasis, we found that destabilizing the GCX through either disturbed flow-induced or enzyme induced GCX degradation results in increased E-selectin receptor-mediated EC-tumor cell interactions.

Conclusion

Our findings lay a foundation for future endothelial GCX-targeted therapy, to control intercellular interactions and limit the progression of atherosclerosis and cancer.

中文翻译：

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内皮糖萼介导的细胞间相互作用：动脉粥样硬化和癌症转移的机制和意义

目的

内皮糖萼 (GCX) 在血管系统的健康中起着关键作用。GCX 的降解与动脉粥样硬化和癌症等疾病的发生有关，因为它破坏了旨在防止动脉粥样硬化和癌症的内皮细胞 (EC) 功能。这种 EC 功能的例子包括通过间隙连接和受体介导的内皮细胞和肿瘤细胞之间的相互作用的内皮细胞间通讯。本综述重点关注健康和患病状态下这些细胞间相互作用的 GCX 依赖性调节。最终目标是建立新知识，可用于开发 GCX 再生策略，控制细胞间相互作用，以对抗动脉粥样硬化和癌症等疾病的进展。

方法

进行了体外和体内研究以确定 GCX 在生理相关条件下的基线表达。采用化学和机械 GCX 降解方法来降解 GCX。使用细胞化学、组织化学、荧光黄染料转移测定以及共聚焦、活体和扫描电子显微镜技术评估完整与降解 GCX 对细胞间相互作用的影响。

结果

与动脉粥样硬化有关，我们发现 GCX 稳定性决定了 Cx43 在间隙连接介导的 EC 到 EC 通信中的表达和功能。与癌症转移相关，我们发现通过扰动流动诱导或酶诱导的 GCX 降解使 GCX 不稳定会导致 E-选择素受体介导的 EC-肿瘤细胞相互作用增加。

结论

我们的发现为未来的内皮 GCX 靶向治疗奠定了基础，以控制细胞间相互作用并限制动脉粥样硬化和癌症的进展。