Endothelial barrier dysfunction in systemic inflammation is mediated by soluble VE-cadherin interfering VE-PTP signaling

Breakdown of endothelial barrier integrity determines organ dysfunction and outcome of patients with sepsis. Increased levels of soluble vascular endothelial (VE)-cadherin fragments (sVE-cadherin) have previously been linked with inflammation-induced loss of endothelial barrier function. We provide...

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Published in:iScience 2023-10, Vol.26 (10), p.108049-108049, Article 108049
Main Authors: Knop, Juna-Lisa, Burkard, Natalie, Danesh, Mahshid, Kintrup, Sebastian, Dandekar, Thomas, Srivastava, Mugdha, Springer, Rebecca, Hiermaier, Matthias, Wagner, Nana-Maria, Waschke, Jens, Flemming, Sven, Schlegel, Nicolas
Format: Article
Language:English
Subjects:
Biological sciences
Cell biology
Molecular biology
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Summary:Breakdown of endothelial barrier integrity determines organ dysfunction and outcome of patients with sepsis. Increased levels of soluble vascular endothelial (VE)-cadherin fragments (sVE-cadherin) have previously been linked with inflammation-induced loss of endothelial barrier function. We provide evidence for a causative role of sVE-cadherin to induce loss of endothelial barrier function. In patients with sepsis, sVE-cadherin levels were associated with organ dysfunction and the need for volume resuscitation. Similarly, LPS-induced systemic inflammation in rats with microvascular dysfunction was paralleled by augmented sVE-cadherin levels. Newly generated recombinant human sVE-cadherin (extracellular domains EC1-5) induced loss of endothelial barrier function in both human microvascular endothelial cells in vitro and in rat mesenteric microvessels in vivo and reduced microcirculatory flow. sVE-cadherinEC1-5 disturbed VE-cadherin-mediated adhesion and perturbed VE-protein tyrosine phosphatase (VE-PTP)/VE-cadherin interaction resulting in RhoGEF1-mediated RhoA activation. VE-PTP inhibitor AKB9778 and Rho-kinase inhibitor Y27632 blunted all sVE-cadherinEC1-5-induced effects, which uncovers a pathophysiological role of sVE-cadherin via dysbalanced VE-PTP/RhoA signaling. [Display omitted] •sVE-cadherin correlates with inflammation-induced endothelial barrier dysfunction•sVE-cadherin has a causative role to induce endothelial barrier dysfunction•sVE-cadherin induces barrier dysfunction by dysbalanced VE-PTP/RhoA signaling Biological sciences; Molecular biology; Cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.108049