Inflammation Research Unit, Division of Internal Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091, Zürich, Switzerland.
Department of Medicine, Uster Hospital, Brunnenstrasse 42, CH-8610, Uster, Switzerland.
Mol Med. 2018 Aug 29;24(1):45. doi: 10.1186/s10020-018-0048-z.
Endothelial barrier dysfunction characterized by hyperpermeability of the vascular endothelium is a key factor in the pathogenesis of chronic inflammatory diseases and affects clinical outcomes. In states of chronic inflammation, mediators secreted by activated immune cells or vascular endothelium may affect the barrier function and permeability of the vascular endothelium. The matricellular R-spondin family member RSPO3 is produced by inflammatory-activated human monocytes and vascular endothelial cells, but its effects in the regulation of vascular endothelial barrier function remains elusive.
The present study investigates the effects of RSPO3 on the barrier function of adult human primary macro- and micro- vascular endothelial monolayers. Tight monolayers of primary endothelial cells from human coronary and pulmonary arteries, and cardiac, brain, and dermal microvascular beds were treated with RSPO3 either alone or in combination with pro-inflammatory mediator IL-1β. Endothelial barrier function was assessed non-invasively in real-time using Electric Cell-substrate Impedance Sensing.
RSPO3 treatment critically affected barrier function by enhancing the permeability of all vascular endothelial monolayers investigated. To confer hyperpermeable phenotype in vascular endothelial monolayers, RSPO3 induced inter-endothelial gap formation by disrupting the β-catenin and VE-cadherin alignment at adherens junctions. RSPO3 synergistically enhanced the barrier impairing properties of the pro-inflammatory mediator IL-1β.
Here, we show that the matricellular protein RSPO3 is a mediator of endothelial hyperpermeability that can act in synergy with the inflammatory mediator IL-1β. This finding stimulates further studies to delineate the endothelial barrier impairing properties of RSPO3 and its synergistic interaction with IL-1β in chronic inflammatory diseases.
血管内皮的通透性增加是慢性炎症性疾病发病机制中的一个关键因素，表现为内皮屏障功能障碍。在慢性炎症状态下，激活的免疫细胞或血管内皮分泌的介质可能会影响血管内皮的屏障功能和通透性。基质细胞 R 卷曲蛋白家族成员 RSPO3 由炎性激活的人单核细胞和血管内皮细胞产生，但它在调节血管内皮屏障功能中的作用仍不清楚。
本研究探讨了 RSPO3 对成人原代大、微血管内皮单层屏障功能的影响。分别用 RSPO3 单独或与促炎介质 IL-1β 联合处理来自人冠状动脉和肺动脉、心脏、脑和皮肤微血管床的原代内皮细胞的紧密单层，以非侵入性实时方式使用电细胞-底物阻抗传感评估内皮屏障功能。
RSPO3 治疗通过增强所有研究的血管内皮单层的通透性，对屏障功能产生了至关重要的影响。为了在血管内皮单层中赋予高通透性表型，RSPO3 通过破坏黏着连接处的β-连环蛋白和 VE-钙黏蛋白排列，诱导内皮细胞间的间隙形成。RSPO3 与促炎介质 IL-1β 协同增强了屏障破坏特性。
本研究表明，基质细胞蛋白 RSPO3 是内皮通透性增加的介质，可与炎症介质 IL-1β 协同作用。这一发现促使进一步研究，以描绘 RSPO3 的内皮屏障破坏特性及其在慢性炎症性疾病中的协同作用与 IL-1β。
