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

Juna-Lisa Knop; Natalie Burkard; Mahshid Danesh; Sebastian Kintrup; Thomas Dandekar; Mugdha Srivastava; Rebecca Springer; Matthias Hiermaier; Nana-Maria Wagner; Jens Waschke; Sven Flemming; Nicolas Schlegel

doi:10.1016/j.isci.2023.108049

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

iScience. 2023 Sep 27;26(10):108049. doi: 10.1016/j.isci.2023.108049. eCollection 2023 Oct 20.

Authors

Affiliations

¹ Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany.
² University of Wuerzburg, Department of Bioinformatics, Biocenter, Am Hubland, D-97074 Wuerzburg, Germany.
³ University Hospital Muenster, Department of Anesthesiology, Intensive Care and Pain Medicine, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
⁴ Core Unit Systems Medicine, 97080 Würzburg, Germany.
⁵ Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany.
⁶ University Hospital Wuerzburg, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany.

Abstract

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-cadherin^EC1-5 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-cadherin^EC1-5-induced effects, which uncovers a pathophysiological role of sVE-cadherin via dysbalanced VE-PTP/RhoA signaling.

Keywords: Biological sciences; Cell biology; Molecular biology.