# 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
\
# 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](https://eprints.gla.ac.uk/view/journal_volume/EBioMedicine.html)*, 107,
105315.
(doi: [10.1016/j.ebiom.2024.105315](https://doi.org/10.1016/j.ebiom.2024.105315))
(PMID:[39216230](https://europepmc.org/abstract/MED/39216230))
(PMCID:[PMC11402910](https://europepmc.org/articles/PMC11402910))
| | |
| --- | --- |
| | [Text](https://eprints.gla.ac.uk/332445/1/332445.pdf) 332445.pdf - Published Version Available under License [Creative Commons Attribution](http://creativecommons.org/licenses/by/4.0/). 2MB |
## 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](https://eprints.gla.ac.uk/view/author/45183.html) and [Hamilton, Dr Graham](https://eprints.gla.ac.uk/view/author/5463.html) and [McClure, Dr John](https://eprints.gla.ac.uk/view/author/7041.html) and [MCNEILLY, Sarah](https://eprints.gla.ac.uk/view/author/40515.html) and [Bulleid, Professor Neil](https://eprints.gla.ac.uk/view/author/11172.html) and [Aman, Dr Alisha](https://eprints.gla.ac.uk/view/author/37653.html) and [Cantini, Dr Marco](https://eprints.gla.ac.uk/view/author/30437.html) and [Boland, Dr Erin](https://eprints.gla.ac.uk/view/author/50415.html) and [Gok, Dr Caglar](https://eprints.gla.ac.uk/view/author/45802.html) and [Lee, Dr Michelle](https://eprints.gla.ac.uk/view/author/66439.html) and [Salmeron-Sanchez, Professor Manuel](https://eprints.gla.ac.uk/view/author/30067.html) and [Graham, Dr Delyth](https://eprints.gla.ac.uk/view/author/3999.html) and [Thomson, Mr Cameron](https://eprints.gla.ac.uk/view/author/81774.html) and [Van Agtmael, Professor Tom](https://eprints.gla.ac.uk/view/author/13057.html) |
| Authors: | [McNeilly, S.](https://eprints.gla.ac.uk/view/author/40515.html), [Thomson, C. R.](https://eprints.gla.ac.uk/view/author/81774.html), Gonzalez-Trueba, L., [Sin, Y. Y.](https://eprints.gla.ac.uk/view/author/45183.html), Granata, A., [Hamilton, G.](https://eprints.gla.ac.uk/view/author/5463.html), [Lee, M.](https://eprints.gla.ac.uk/view/author/66439.html), [Boland, E.](https://eprints.gla.ac.uk/view/author/50415.html), [McClure, J. D.](https://eprints.gla.ac.uk/view/author/7041.html), Lumbreras Perales, C., [Aman, A.](https://eprints.gla.ac.uk/view/author/37653.html), Kumar, A. A., [Cantini, M.](https://eprints.gla.ac.uk/view/author/30437.html), [Gok, C.](https://eprints.gla.ac.uk/view/author/45802.html), [Graham, D.](https://eprints.gla.ac.uk/view/author/3999.html), Tomono, Y., Anderson, C. D., Lu, Y., Smith, C., Markus, H. S., Abramowicz, M., Vilain, C., Al-Shahi Salman, R., [Salmeron-Sanchez, M.](https://eprints.gla.ac.uk/view/author/30067.html), Hainsworth, A. H., Fuller, W., Kadler, K. E., [Bulleid, N. J.](https://eprints.gla.ac.uk/view/author/11172.html), and [Van Agtmael, T.](https://eprints.gla.ac.uk/view/author/13057.html) |
| College/School: | [College of Medical Veterinary and Life Sciences](https://eprints.gla.ac.uk/view/divisions/20000000/) [College of Medical Veterinary and Life Sciences](https://eprints.gla.ac.uk/view/divisions/20000000/) > [School of Cardiovascular & Metabolic Health](https://eprints.gla.ac.uk/view/divisions/25200000/) [College of Medical Veterinary and Life Sciences](https://eprints.gla.ac.uk/view/divisions/20000000/) > [School of Molecular Biosciences](https://eprints.gla.ac.uk/view/divisions/25400000/) [College of Science and Engineering](https://eprints.gla.ac.uk/view/divisions/30000000/) > [School of Engineering](https://eprints.gla.ac.uk/view/divisions/30300000/) > [Biomedical Engineering](https://eprints.gla.ac.uk/view/divisions/30303000/) |
| Journal Name: | [EBioMedicine](https://eprints.gla.ac.uk/view/journal_volume/EBioMedicine.html) |
| 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 |
University Staff: [Request a correction](https://eprints.gla.ac.uk/cgi/request_correction?eprintid=332445) | Enlighten Editors: [Update this record](https://eprints.gla.ac.uk/cgi/users/home?screen=EPrint::View&eprintid=332445)
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
[172199](https://eprints.gla.ac.uk/view/project_code/172199.html)
BHF 4 Year PhD Studentship Award (3rd intake 2015)
Rhian Touyz
[British Heart Foundation (BHF)](https://eprints.gla.ac.uk/view/funder/British_Heart_Foundation_=28BHF=29.html)
FS/15/64/32035
School of Cardiovascular & Metabolic Health
[172813](https://eprints.gla.ac.uk/view/project_code/172813.html)
Targeting intracellular pathways to dissect mechanisms of cerebrovascular disease.
Tom Van Agtmael
[British Heart Foundation (BHF)](https://eprints.gla.ac.uk/view/funder/British_Heart_Foundation_=28BHF=29.html)
PG/15/92/31813
School of Cardiovascular & Metabolic Health
[302164](https://eprints.gla.ac.uk/view/project_code/302164.html)
Collagen IV variants and their role in intracerebral haemorrhage in the general population
Tom Van Agtmael
[Medical Research Council (MRC)](https://eprints.gla.ac.uk/view/funder/Medical_Research_Council_=28MRC=29.html)
MR/R005567/1
SCMH - Cardiovascular & Metabolic Health
[300478](https://eprints.gla.ac.uk/view/project_code/300478.html)
Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutations
Tom Van Agtmael
[Heart Research UK (HEARTRES)](https://eprints.gla.ac.uk/view/funder/Heart_Research_UK_=28HEARTRES=29.html)
RG 2664/17/20
SCMH - Cardiovascular & Metabolic Health
[190840](https://eprints.gla.ac.uk/view/project_code/190840.html)
Protein Folding and Thiol Modification in the Mammalian Endoplasmic Reticulum
Neil Bulleid
[Wellcome Trust (WELLCOTR)](https://eprints.gla.ac.uk/view/funder/Wellcome_Trust_=28WELLCOTR=29.html)
103720/Z/14/Z
SMB - Molecular Biosciences
[303613](https://eprints.gla.ac.uk/view/project_code/303613.html)
Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair
Marco Cantini
[Medical Research Council (MRC)](https://eprints.gla.ac.uk/view/funder/Medical_Research_Council_=28MRC=29.html)
MR/S005412/1
ENG - Biomedical Engineering
Deposit and Record Details
[Deposit and Record Details](#)
[Deposit and Record Details](#)
| | |
| --- | --- |
| ID Code: | 332445 |
| Depositing User: | [Dr Mary Donaldson](https://eprints.gla.ac.uk/profile/9223) |
| 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 |
Download Statistics
[Download Statistics](#)
[Download Statistics](#)
Downloads per month over past year
[View more statistics](#)