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Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction
Cathrin E Hansen1,2,3, Davide Vacondio4,5, Lennart van der Molen4,6
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. c.e.hansen@amsterdamumc.nl.
Brain endothelial cell aging, driven by DNA damage repair defects (ERCC1 deficiency), impairs blood-brain barrier integrity and promotes neuroinflammation. This cellular aging contributes to cognitive decline and brain homeostasis disruption.
Area of Science:
- Neuroscience
- Cellular Biology
- Genetics
Background:
- Brain vasculature aging is linked to neurovascular and neurodegenerative diseases.
- Endothelial cell (EC) genomic instability's role in brain homeostasis is poorly understood.
- DNA damage significantly accelerates cellular aging.
Purpose of the Study:
- Investigate how endothelial aging affects blood-brain barrier (BBB) function.
- Examine the impact of DNA repair deficiency in brain ECs on BBB integrity and brain homeostasis.
Main Methods:
- Utilized ERCC1-deficient human brain ECs in vitro.
- Employed an EC-specific Ercc1 knock out (EC-KO) mouse model.
- Assessed BBB integrity, senescence markers, angiogenic pathways, and immune cell infiltration.
Main Results:
- ERCC1-deficient ECs showed senescence, reduced BBB integrity, and increased sprouting via Dll4-Notch pathway dysregulation.
- EC-KO mice exhibited increased P21+ cells, angiogenic markers, ECs, and pericytes.
- EC-KO mice displayed BBB leakage, immune cell infiltration into white matter, and enhanced adhesion molecule expression.
Conclusions:
- Endothelial aging, linked to ERCC1 deficiency, drives BBB dysfunction.
- Endothelial aging promotes sprouting and immune cell migration into the brain.
- These aging-related changes contribute to impaired brain homeostasis.
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