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RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1


Skaria, Tom; Bachli, Esther; Schoedon, Gabriele (2018). RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1. Molecular Medicine:24:45.

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. KEYWORDS: Endothelial dysfunction; IL-1β; Inflammation; RSPO3; Vascular leakage

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. KEYWORDS: Endothelial dysfunction; IL-1β; Inflammation; RSPO3; Vascular leakage

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Contributors:Department of Medicine, Uster Hospital, Brunnenstrasse 42, CH-8610, Uster, Switzerland
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2018
Deposited On:13 Sep 2018 11:24
Last Modified:24 Sep 2019 23:36
Publisher:The Feinstein Institute for Medical Research
ISSN:1076-1551
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/s10020-018-0048-z
PubMed ID:30157748
Project Information:
  • : FunderSwiss National Science Foundation
  • : Grant ID31–124861
  • : Project Title

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