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The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation

Lookup NU author(s): Dr Sarah Withers

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2025. Published by The Company of Biologists. The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, have been associated with vascular pathology. Viral infections have been linked to intracerebral haemorrhage (ICH) risk, but the molecular mechanisms leading to ICH via antiviral responses remain unknown. We hypothesised that the CH25H/25HC pathway impacts neuroendothelial integrity in the context of infection-associated ICH. Using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified upregulation of CH25H in infection-associated cerebral haemorrhage. Using zebrafish models and human brain endothelial cells, we asked whether 25HC promotes neurovascular dysfunction by modulating cholesterol metabolism. We found that 25HC and pharmacological inhibition of cholesterol synthesis had an additive effect to exacerbate brain bleeding in zebrafish and in vitro neuroendothelial dysfunction. 25HC-induced dysfunction was also rescued by cholesterol supplementation in vitro. These results demonstrate that 25HC can dysregulate brain endothelial function by remodelling cholesterol metabolism. We propose that CH25H/25HC plays an important role in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.

Publication metadata

Author(s): Tapia VS, Withers SE, Zhou R, Bennington A, Hoyle C, Hedley F, El Khouja A, Luka N, Massimo M, Crilly S, Long KR, Lawrence CB, Kasher PR

Publication type: Article

Publication status: Published

Journal: Disease Models & Mechanisms

Year: 2025

Volume: 18

Issue: 9

Print publication date: 01/09/2025

Online publication date: 23/05/2025

Acceptance date: 28/04/2025

Date deposited: 09/06/2025

ISSN (print): 1754-8403

ISSN (electronic): 1754-8411

Publisher: The Company of Biologists Ltd

URL: https://doi.org/10.1242/dmm.052145

DOI: 10.1242/dmm.052145

Data Access Statement: All relevant data can be found within the article and its supplementary information.

PubMed id: 40406995

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