Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment.

Autor: Manukjan N; Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Majcher D; Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Leenders P; Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Caiment F; Department of Toxicogenomics, GROW-School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., van Herwijnen M; Department of Toxicogenomics, GROW-School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Smeets HJ; Department of Toxicogenomics, GROW-School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Suidgeest E; C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, P.O. Box 9500, 2300 RA, Leiden, the Netherlands., van der Weerd L; C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, P.O. Box 9500, 2300 RA, Leiden, the Netherlands.; Department of Human Genetics, Leiden University Medical Center, P.O. Box 9500, 2300 RA, Leiden, The Netherlands., Vanmierlo T; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Neuroscience, Biomedical Research Institute, Hasselt University, 3500, Hasselt, Belgium.; Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Jansen JFA; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands., Backes WH; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands., van Oostenbrugge RJ; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Neurology, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands., Staals J; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Neurology, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands., Fulton D; Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Ahmed Z; Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. z.ahmed.1@bham.ac.uk.; Centre for Trauma Sciences Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. z.ahmed.1@bham.ac.uk., Blankesteijn WM; Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Foulquier S; Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; CARIM - School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; MHeNs-School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.; Department of Neurology, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2023 Aug 07; Vol. 11 (1), pp. 128. Date of Electronic Publication: 2023 Aug 07.
DOI: 10.1186/s40478-023-01627-5
Abstrakt: 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 Hif1α 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 Hif1α/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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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