| Autor: |
Sarah McNeilly, Cameron R. Thomson, Laura Gonzalez-Trueba, Yuan Yan Sin, Alessandra Granata, Graham Hamilton, Michelle Lee, Erin Boland, John D. McClure, Cristina Lumbreras-Perales, Alisha Aman, Apoorva A. Kumar, Marco Cantini, Caglar Gök, Delyth Graham, Yasuko Tomono, Christopher D. Anderson, Yinhui Lu, Colin Smith, Hugh S. Markus, Marc Abramowicz, Catheline Vilain, Rustam Al-Shahi Salman, Manuel Salmeron-Sanchez, Atticus H. Hainsworth, William Fuller, Karl E. Kadler, Neil J. Bulleid, Tom Van Agtmael |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
EBioMedicine, Vol 107, Iss , Pp 105315- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2352-3964 |
| DOI: |
10.1016/j.ebiom.2024.105315 |
| Popis: |
Summary: Background: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure. Methods: Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH. Findings: Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca2+-sensitive K+ channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca2+ levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles. Interpretation: COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets. Funding: MRC, Wellcome Trust, BHF. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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