Jan Wenzel1,2, Dimitrios Spyropoulos1,2, Julian Christopher Assmann1, Mahtab Ahmad Khan1, Ines Stölting1, Beate Lembrich1, Sara Kreißig1, Dirk Andreas Ridder3, Berend Isermann4, Markus Schwaninger1,2. 1. Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Germany (J.W., D.S., J.C.A., M.A.K., I.S., B.L., S.K., M.S.). 2. German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany (J.W., D.S., M.S.). 3. Institute of Pathology, Mainz University Medical Center, Germany (D.A.R.). 4. Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Germany (B.I.).
Abstract
OBJECTIVE: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. CONCLUSIONS: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.
OBJECTIVE:THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. CONCLUSIONS: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.
Authors: Jonathan Douxfils; Julien Favresse; Jean-Michel Dogné; Thomas Lecompte; Sophie Susen; Charlotte Cordonnier; Aurélien Lebreton; Robert Gosselin; Pierre Sié; Gilles Pernod; Yves Gruel; Philippe Nguyen; Caroline Vayne; François Mullier Journal: Thromb Res Date: 2021-05-15 Impact factor: 3.944
Authors: Marijana Sekulic-Jablanovic; Jessica Paproth; Cinzia Sgambato; Giuseppe Albano; Daniel G Fuster; Daniel Bodmer; Vesna Petkovic Journal: Front Cell Neurosci Date: 2022-04-12 Impact factor: 5.505
Authors: Magdalena L Bochenek; Rajinikanth Gogiraju; Stefanie Großmann; Janina Krug; Jennifer Orth; Sabine Reyda; George S Georgiadis; Henri M Spronk; Stavros Konstantinides; Thomas Münzel; John H Griffin; Philipp Wild; Christine Espinola-Klein; Wolfram Ruf; Katrin Schäfer Journal: JCI Insight Date: 2022-07-22