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
Affiliations
Juna-Lisa Knop
Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany
Natalie Burkard
Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany
Mahshid Danesh
University of Wuerzburg, Department of Bioinformatics, Biocenter, Am Hubland, D-97074 Wuerzburg, Germany
Sebastian Kintrup
University Hospital Muenster, Department of Anesthesiology, Intensive Care and Pain Medicine, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
Thomas Dandekar
University of Wuerzburg, Department of Bioinformatics, Biocenter, Am Hubland, D-97074 Wuerzburg, Germany
Mugdha Srivastava
Core Unit Systems Medicine, 97080 Würzburg, Germany
Rebecca Springer
Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany
Matthias Hiermaier
Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany
Nana-Maria Wagner
University Hospital Muenster, Department of Anesthesiology, Intensive Care and Pain Medicine, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; University Hospital Wuerzburg, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany
Jens Waschke
Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany
Sven Flemming
Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany
Nicolas Schlegel
Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Oberduerrbacherstraße 6, D-97080 Wuerzburg, Germany; Corresponding author
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.
