Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment. Manukjan, N., Majcher, D., Leenders, P., Caiment, F., van Herwijnen, M., Smeets, H. J., Suidgeest, E., van der Weerd, L., Vanmierlo, T., Jansen, J. F. A., Backes, W. H., van Oostenbrugge, R. J., Staals, J., Fulton, D., Ahmed, Z., Blankesteijn, W. M., & Foulquier, S. Acta Neuropathol Commun, 11(1):128, 2023. Manukjan, Narek Majcher, Daria Leenders, Peter Caiment, Florian van Herwijnen, Marcel Smeets, Hubert J Suidgeest, Ernst van der Weerd, Louise Vanmierlo, Tim Jansen, Jacobus F A Backes, Walter H van Oostenbrugge, Robert J Staals, Julie Fulton, Daniel Ahmed, Zubair Blankesteijn, W Matthijs Foulquier, Sebastien eng 017.009.048/Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ 2013(1)-195/Hersenstichting/ Joint Fellowship/CARIM School for Cardiovascular Diseases, Universiteit Maastricht/ Joint Fellowship/University of Birmingham/ Out of the Box Ideas/CardioVasculair Onderzoek Nederland (CVON)/ England Acta Neuropathol Commun. 2023 Aug 7;11(1):128. doi: 10.1186/s40478-023-01627-5.![Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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 Hif1alpha 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 Hif1alpha/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.
@article{RN335,
author = {Manukjan, N. and Majcher, D. and Leenders, P. and Caiment, F. and van Herwijnen, M. and Smeets, H. J. and Suidgeest, E. and van der Weerd, L. and Vanmierlo, T. and Jansen, J. F. A. and Backes, W. H. and van Oostenbrugge, R. J. and Staals, J. and Fulton, D. and Ahmed, Z. and Blankesteijn, W. M. and Foulquier, S.},
title = {Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment},
journal = {Acta Neuropathol Commun},
volume = {11},
number = {1},
pages = {128},
note = {Manukjan, Narek
Majcher, Daria
Leenders, Peter
Caiment, Florian
van Herwijnen, Marcel
Smeets, Hubert J
Suidgeest, Ernst
van der Weerd, Louise
Vanmierlo, Tim
Jansen, Jacobus F A
Backes, Walter H
van Oostenbrugge, Robert J
Staals, Julie
Fulton, Daniel
Ahmed, Zubair
Blankesteijn, W Matthijs
Foulquier, Sebastien
eng
017.009.048/Nederlandse Organisatie voor Wetenschappelijk Onderzoek/
2013(1)-195/Hersenstichting/
Joint Fellowship/CARIM School for Cardiovascular Diseases, Universiteit Maastricht/
Joint Fellowship/University of Birmingham/
Out of the Box Ideas/CardioVasculair Onderzoek Nederland (CVON)/
England
Acta Neuropathol Commun. 2023 Aug 7;11(1):128. doi: 10.1186/s40478-023-01627-5.},
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 Hif1alpha 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 Hif1alpha/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.},
keywords = {Humans
Mice
Animals
Blood-Brain Barrier/metabolism
*Oligodendrocyte Precursor Cells/metabolism
*White Matter/pathology
Hypoxia/metabolism
*Cerebral Small Vessel Diseases/pathology
Vascular Endothelial Growth Factor A/metabolism
Angiogenesis
Bbb
Glial biology
Opc
Vascular dementia
cSVD
content of this article.},
ISSN = {2051-5960 (Electronic)
2051-5960 (Linking)},
DOI = {10.1186/s40478-023-01627-5},
url = {https://www.ncbi.nlm.nih.gov/pubmed/37550790},
year = {2023},
type = {Journal Article}
}
Downloads: 0
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M.","Foulquier, S."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Manukjan"],"firstnames":["N."],"suffixes":[]},{"propositions":[],"lastnames":["Majcher"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Leenders"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Caiment"],"firstnames":["F."],"suffixes":[]},{"propositions":["van"],"lastnames":["Herwijnen"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Smeets"],"firstnames":["H.","J."],"suffixes":[]},{"propositions":[],"lastnames":["Suidgeest"],"firstnames":["E."],"suffixes":[]},{"propositions":["van","der"],"lastnames":["Weerd"],"firstnames":["L."],"suffixes":[]},{"propositions":[],"lastnames":["Vanmierlo"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Jansen"],"firstnames":["J.","F.","A."],"suffixes":[]},{"propositions":[],"lastnames":["Backes"],"firstnames":["W.","H."],"suffixes":[]},{"propositions":["van"],"lastnames":["Oostenbrugge"],"firstnames":["R.","J."],"suffixes":[]},{"propositions":[],"lastnames":["Staals"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Fulton"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Ahmed"],"firstnames":["Z."],"suffixes":[]},{"propositions":[],"lastnames":["Blankesteijn"],"firstnames":["W.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Foulquier"],"firstnames":["S."],"suffixes":[]}],"title":"Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment","journal":"Acta Neuropathol Commun","volume":"11","number":"1","pages":"128","note":"Manukjan, Narek Majcher, Daria Leenders, Peter Caiment, Florian van Herwijnen, Marcel Smeets, Hubert J Suidgeest, Ernst van der Weerd, Louise Vanmierlo, Tim Jansen, Jacobus F A Backes, Walter H van Oostenbrugge, Robert J Staals, Julie Fulton, Daniel Ahmed, Zubair Blankesteijn, W Matthijs Foulquier, Sebastien eng 017.009.048/Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ 2013(1)-195/Hersenstichting/ Joint Fellowship/CARIM School for Cardiovascular Diseases, Universiteit Maastricht/ Joint Fellowship/University of Birmingham/ Out of the Box Ideas/CardioVasculair Onderzoek Nederland (CVON)/ England Acta Neuropathol Commun. 2023 Aug 7;11(1):128. doi: 10.1186/s40478-023-01627-5.","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 Hif1alpha 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 Hif1alpha/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. 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