Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage.

Autor:	McNeilly S; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Thomson CR; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Gonzalez-Trueba L; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Sin YY; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Granata A; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK., Hamilton G; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Glasgow Polyomics, University of Glasgow, Glasgow, UK., Lee M; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Boland E; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., McClure JD; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Lumbreras-Perales C; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Aman A; School of Health and Wellbeing, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Kumar AA; Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK; Princess Royal University Hospital, Kings College Hospital NHS Foundation Trust, London, UK., Cantini M; Centre for the Cellular Microenvironment, School of Science and Engineering, University of Glasgow, Glasgow, UK., Gök C; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Graham D; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Tomono Y; Division of Molecular & Cell Biology, Shigei Medical Research Institute, Okayama, Japan., Anderson CD; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Lu Y; Wellcome Centre for Cell Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK., Smith C; Academic Neuropathology, University of Edinburgh, Edinburgh, UK., Markus HS; Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Abramowicz M; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium., Vilain C; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium., Al-Shahi Salman R; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK., Salmeron-Sanchez M; Centre for the Cellular Microenvironment, School of Science and Engineering, University of Glasgow, Glasgow, UK., Hainsworth AH; Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK., Fuller W; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK., Kadler KE; Wellcome Centre for Cell Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK., Bulleid NJ; School of Molecular Biosciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Van Agtmael T; School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: tom.vanagtmael@glasgow.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Sep; Vol. 107, pp. 105315. Date of Electronic Publication: 2024 Aug 30.
DOI:	10.1016/j.ebiom.2024.105315
Abstrakt:	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 Ca 2+ -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 Ca 2+ 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. Competing Interests: Declaration of interests CDA reports sponsored research support from the American Heart Association (18SFRN34250007 and 21SFRN812095) and Bayer AG, and consulting with ApoPharma, outside the scope of the current work. RA-SS reports grants outside the submitted work from BHF, Chief Scientist Office of the Scottish Government, and National Institutes of Health Research Health Technology Assessment programme paid to The University of Edinburgh, consultancy income paid to The University from Recursion Pharmaceuticals, and reimbursement for endpoint adjudication paid to The University of Edinburgh from NovoNordisk. TVA reports he serves on the grants committee of DEBRA UK and was honorary Treasurer for the British Society of Matrix Biology (2016–2022). (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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