Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage
Source: https://eprints.gla.ac.uk/332445/ Parent: https://eprints.gla.ac.uk/view/project_code/303613.html
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Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage
McNeilly, S. et al. (2024) Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage. EBioMedicine, 107, 105315. (doi: 10.1016/j.ebiom.2024.105315) (PMID:39216230) (PMCID:PMC11402910)
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Abstract
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.
| Item Type: | Articles |
| Additional Information: | This work was made possible thanks to: British Heart Foundation (BHF) studentship to SJM (FS/15/64/32035); grants from BHF (PG/15/92/31813), UK Medical Research Council (MRC) (MR/R005567/1), Stroke Association (16VAD_04) and Heart Research UK (RG 2664/17/20) to TVA, fellowships for LINCHPIN from UK MRC (G0900428 and G1002605) to RA-SS, funding from Wellcome Trust (103720) to NJB, Wellcome Trust (110126/Z/15/Z, 203128/Z/16/Z) to KEK, MRC (MR/S005412/1) to MC, and NIH-NINDS (R01NS103924) to CDA. |
| Keywords: | Collagen, basement membrane, cerebrovascular disease, stroke, small vessel disease, endothelial dysfunction. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sin, Dr Angie and Hamilton, Dr Graham and McClure, Dr John and MCNEILLY, Sarah and Bulleid, Professor Neil and Aman, Dr Alisha and Cantini, Dr Marco and Boland, Dr Erin and Gok, Dr Caglar and Lee, Dr Michelle and Salmeron-Sanchez, Professor Manuel and Graham, Dr Delyth and Thomson, Mr Cameron and Van Agtmael, Professor Tom |
| Authors: | McNeilly, S., Thomson, C. R., Gonzalez-Trueba, L., Sin, Y. Y., Granata, A., Hamilton, G., Lee, M., Boland, E., McClure, J. D., Lumbreras Perales, C., Aman, A., Kumar, A. A., Cantini, M., Gok, C., Graham, D., Tomono, Y., Anderson, C. D., Lu, Y., Smith, C., Markus, H. S., Abramowicz, M., Vilain, C., Al-Shahi Salman, R., Salmeron-Sanchez, M., Hainsworth, A. H., Fuller, W., Kadler, K. E., Bulleid, N. J., and Van Agtmael, T. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Science and Engineering > School of Engineering > Biomedical Engineering |
| Journal Name: | EBioMedicine |
| Publisher: | Elsevier |
| ISSN: | 2352-3964 |
| ISSN (Online): | 2352-3964 |
| Copyright Holders: | Copyright: © 2024 The Author(s) |
| First Published: | First published in EBioMedicine 107: 105315 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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Funder and Project Information
Funder and Project Information
Funder and Project Information
Project Code
Award No
Project Name
Principal Investigator
Funder's Name
Funder Ref
Lead Dept
BHF 4 Year PhD Studentship Award (3rd intake 2015)
Rhian Touyz
British Heart Foundation (BHF)
FS/15/64/32035
School of Cardiovascular & Metabolic Health
Targeting intracellular pathways to dissect mechanisms of cerebrovascular disease.
Tom Van Agtmael
British Heart Foundation (BHF)
PG/15/92/31813
School of Cardiovascular & Metabolic Health
Collagen IV variants and their role in intracerebral haemorrhage in the general population
Tom Van Agtmael
Medical Research Council (MRC)
MR/R005567/1
SCMH - Cardiovascular & Metabolic Health
Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutations
Tom Van Agtmael
RG 2664/17/20
SCMH - Cardiovascular & Metabolic Health
Protein Folding and Thiol Modification in the Mammalian Endoplasmic Reticulum
Neil Bulleid
103720/Z/14/Z
SMB - Molecular Biosciences
Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair
Marco Cantini
Medical Research Council (MRC)
MR/S005412/1
ENG - Biomedical Engineering
Deposit and Record Details
| ID Code: | 332445 |
| Depositing User: | Dr Mary Donaldson |
| Datestamp: | 16 Aug 2024 11:45 |
| Last Modified: | 10 Feb 2026 12:02 |
| Date of acceptance: | 14 August 2024 |
| Date of first online publication: | 30 August 2024 |
| Date Deposited: | 16 August 2024 |
| Data Availability Statement: | Yes |
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