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Title: | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment | Authors: | Manukjan, Narek Majcher, Daria Leenders, Peter Caiment, Florian van Herwijnen, Marcel Smeets, Hubert J. J. Suidgeest, Ernst van der Weerd, Louise VANMIERLO, Tim Jansen, Jacobus F. A. Backes, Walter H. H. van Oostenbrugge, Robert J. J. Staals, Julie Fulton, Daniel Ahmed, Zubair Blankesteijn, W. Matthijs Foulquier, Sebastien |
Issue Date: | 2023 | Publisher: | BMC | Source: | Acta Neuropathologica Communications, 11 (1) (Art N° 128) | Abstract: | Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood-brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell-endothelial cell signalling leading to blood-brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood-brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood-brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood-brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1 & alpha; and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood-brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1 & alpha;/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood-brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease. | Notes: | Ahmed, Z (corresponding author), Univ Birmingham, Inst Inflammat & Ageing, Neurosci & Ophthalmol, Birmingham B15 2TT, England.; Ahmed, Z (corresponding author), Univ Birmingham, Ctr Trauma Sci Res, Birmingham B15 2TT, England. z.ahmed.1@bham.ac.uk |
Keywords: | Vascular dementia;Glial biology;OPC;Angiogenesis;BBB;cSVD | Document URI: | http://hdl.handle.net/1942/41631 | ISSN: | 2051-5960 | e-ISSN: | 2051-5960 | DOI: | 10.1186/s40478-023-01627-5 | ISI #: | 001042657400001 | Rights: | The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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