학술논문
Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood-brain barrier dysfunction.
Document Type
Academic Journal
Author
Schumacher S; Department of Basic and Applied Medical Sciences - Physiology Group, Ghent University, Ghent, Belgium.; Tahiri H; Department of Basic and Applied Medical Sciences - Physiology Group, Ghent University, Ghent, Belgium.; Ezan P; Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, Université PSL, Labex Memolife, Paris, France.; Rouach N; Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, Université PSL, Labex Memolife, Paris, France.; Witschas K; Department of Basic and Applied Medical Sciences - Physiology Group, Ghent University, Ghent, Belgium.; Leybaert L; Department of Basic and Applied Medical Sciences - Physiology Group, Ghent University, Ghent, Belgium.
Source
Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8806785 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-1136 (Electronic) Linking ISSN: 08941491 NLM ISO Abbreviation: Glia Subsets: MEDLINE
Subject
Language
English
Abstract
Therapeutic brain irradiation with ionizing radiation exerts multiple side effects including barrier leakage that disturbs glial-neuronal functioning and may affect cognition. Astrocytes contribute to barrier leakage by endfeet release of various vasoactive substances acting on capillary endothelial cells forming the barrier. Here, we investigated X-ray effects on astrocytic vesicular transport in mice and determined whether interfering with astrocyte connexins affects radiation-induced barrier leakage. We found that astrocytic VEGF-A-loaded VAMP3 vesicles drastically reorganize starting from 6 h post-irradiation and move in a calcium- and Cx43-dependent manner towards endfeet where VEGF-A is released, provoking barrier leakage. Vesicular transport activation, VEGF-A release and leakage 24 h post-irradiation were all potently inhibited by astrocytic Cx43 KO, Cx43S255/262/279/282A (MK4) mutant mice and TATGap19 inhibition of Cx43 hemichannel opening. Astrocyte VEGF release is a major player in complications of brain irradiation, which can be mitigated by anti-VEGF treatments. Targeting Cx43 hemichannels allows to prevent astrocyte VEGF release at an early stage after brain irradiation.
(© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)
(© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)