25-hydroxycholesterol dysregulates brain endothelial cell function and exacerbates cerebral haemorrhage

TY - UNPB

T1 - 25-hydroxycholesterol dysregulates brain endothelial cell function and exacerbates cerebral haemorrhage

AU - Tapia, Victor S

AU - Withers, Sarah

AU - Zhou, Ran

AU - Bennington, Abigail

AU - Hedley, Frances

AU - El Khouja, Adam

AU - Luka, Nadim

AU - Massimo, Marco

AU - Crilly, Siobhan

AU - Long, Katherine

AU - Lawrence, Catherine B.

AU - Kasher, Paul

PY - 2024/5/10

Y1 - 2024/5/10

N2 - Viral infection and hypocholesterolaemia are two independent risk factors for intracerebral haemorrhage (ICH), but the molecular mechanisms leading to vascular rupture via these risk factors remain unknown. We hypothesised that the enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, may offer a mechanistic link between cholesterol dysregulation and infection during neurovascular dysfunction. We identified an upregulation of CH25H in infection-associated cerebral haemorrhage, in a SARS-CoV-2-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical microbleeds. Using human brain endothelial cells and zebrafish ICH models, we show that 25HC promotes endothelial dysfunction and exacerbates brain bleeding. These effects involved cholesterol metabolism modulation, as cholesterol supplementation rescued these effects, while 25HC and statin treatments interacted to exacerbate dysfunction. We propose that the CH25H/25HC pathway represents an important component in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.

AB - Viral infection and hypocholesterolaemia are two independent risk factors for intracerebral haemorrhage (ICH), but the molecular mechanisms leading to vascular rupture via these risk factors remain unknown. We hypothesised that the enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, may offer a mechanistic link between cholesterol dysregulation and infection during neurovascular dysfunction. We identified an upregulation of CH25H in infection-associated cerebral haemorrhage, in a SARS-CoV-2-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical microbleeds. Using human brain endothelial cells and zebrafish ICH models, we show that 25HC promotes endothelial dysfunction and exacerbates brain bleeding. These effects involved cholesterol metabolism modulation, as cholesterol supplementation rescued these effects, while 25HC and statin treatments interacted to exacerbate dysfunction. We propose that the CH25H/25HC pathway represents an important component in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.

U2 - 10.1101/2024.05.10.590792

DO - 10.1101/2024.05.10.590792

M3 - Preprint

T3 - bioRxiv

BT - 25-hydroxycholesterol dysregulates brain endothelial cell function and exacerbates cerebral haemorrhage

PB - Cold Spring Harbor Laboratory Press

ER -