Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment
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—en...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01627-5 |
| _version_ | 1797451142515392512 |
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| author | Narek Manukjan Daria Majcher Peter Leenders Florian Caiment Marcel van Herwijnen Hubert J. Smeets Ernst Suidgeest Louise van der Weerd Tim Vanmierlo Jacobus F. A. Jansen Walter H. Backes Robert J. van Oostenbrugge Julie Staals Daniel Fulton Zubair Ahmed W. Matthijs Blankesteijn Sébastien Foulquier |
| author_facet | Narek Manukjan Daria Majcher Peter Leenders Florian Caiment Marcel van Herwijnen Hubert J. Smeets Ernst Suidgeest Louise van der Weerd Tim Vanmierlo Jacobus F. A. Jansen Walter H. Backes Robert J. van Oostenbrugge Julie Staals Daniel Fulton Zubair Ahmed W. Matthijs Blankesteijn Sébastien Foulquier |
| author_sort | Narek Manukjan |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-09T14:50:34Z |
| format | Article |
| id | doaj.art-a3555923891f4aa483f56460bea38e71 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-09T14:50:34Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a3555923891f4aa483f56460bea38e712023-11-26T14:31:59ZengBMCActa Neuropathologica Communications2051-59602023-08-0111111710.1186/s40478-023-01627-5Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairmentNarek Manukjan0Daria Majcher1Peter Leenders2Florian Caiment3Marcel van Herwijnen4Hubert J. Smeets5Ernst Suidgeest6Louise van der Weerd7Tim Vanmierlo8Jacobus F. A. Jansen9Walter H. Backes10Robert J. van Oostenbrugge11Julie Staals12Daniel Fulton13Zubair Ahmed14W. Matthijs Blankesteijn15Sébastien Foulquier16Department of Pharmacology and Toxicology, Maastricht UniversityDepartment of Pharmacology and Toxicology, Maastricht UniversityDepartment of Pharmacology and Toxicology, Maastricht UniversityDepartment of Toxicogenomics, GROW–School for Oncology and Developmental Biology, Maastricht UniversityDepartment of Toxicogenomics, GROW–School for Oncology and Developmental Biology, Maastricht UniversityDepartment of Toxicogenomics, GROW–School for Oncology and Developmental Biology, Maastricht UniversityC.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical CenterC.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical CenterMHeNs—School for Mental Health and Neuroscience, Maastricht UniversityMHeNs—School for Mental Health and Neuroscience, Maastricht UniversityCARIM - School for Cardiovascular Diseases, Maastricht UniversityCARIM - School for Cardiovascular Diseases, Maastricht UniversityCARIM - School for Cardiovascular Diseases, Maastricht UniversityNeuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of BirminghamNeuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of BirminghamDepartment of Pharmacology and Toxicology, Maastricht UniversityDepartment of Pharmacology and Toxicology, Maastricht UniversityAbstract 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.https://doi.org/10.1186/s40478-023-01627-5Vascular dementiaGlial biologyOPCAngiogenesisBBBcSVD |
| spellingShingle | Narek Manukjan Daria Majcher Peter Leenders Florian Caiment Marcel van Herwijnen Hubert J. Smeets Ernst Suidgeest Louise van der Weerd Tim Vanmierlo Jacobus F. A. Jansen Walter H. Backes Robert J. van Oostenbrugge Julie Staals Daniel Fulton Zubair Ahmed W. Matthijs Blankesteijn Sébastien Foulquier Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment Acta Neuropathologica Communications Vascular dementia Glial biology OPC Angiogenesis BBB cSVD |
| title | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment |
| title_full | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment |
| title_fullStr | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment |
| title_full_unstemmed | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment |
| title_short | Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment |
| title_sort | hypoxic oligodendrocyte precursor cell derived vegfa is associated with blood brain barrier impairment |
| topic | Vascular dementia Glial biology OPC Angiogenesis BBB cSVD |
| url | https://doi.org/10.1186/s40478-023-01627-5 |
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