Biomechanical and compositional basement membrane defects due to a Col4a1 mutation affect cardiac morphology and function
Source: https://eprints.gla.ac.uk/366006/ Parent: https://eprints.gla.ac.uk/view/project_code/303613.html
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Biomechanical and compositional basement membrane defects due to a Col4a1 mutation affect cardiac morphology and function
Boland, E. et al. (2025) Biomechanical and compositional basement membrane defects due to a Col4a1 mutation affect cardiac morphology and function. Matrix Biology, 141, pp. 82-100. (doi: 10.1016/j.matbio.2025.09.003) (PMID:40946812)
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Abstract
Collagen IV is a major constituent of basement membranes and mutations in the genes COL4A1 and COL4A2 present clinically as a variable, multi-system disorder called COL4A1 (Gould) syndrome. Evidence from case reports supports a cardiac component to this disease, but the phenotypic and functional implications affecting the heart, their progression and underlying mechanisms all remain poorly characterised. Indeed, the role of the basement membrane (BM) in adult cardiac disease remains underexplored. We set out to address these knowledge gaps by combining in-depth phenotypic and molecular analyses of a Col4a1 mutation on cardiac biology in a murine model (Col4a1+/svc) of Gould Syndrome. This revealed morphological cardiac defects including cardiomyocyte hypertrophy with myocardial and vascular fibrotic remodelling that impaired cardiac function. The Col4a1 mutation causes systolic and diastolic dysfunction with reduced left ventricular developed pressure. Mechanistically, we show these defects are due to secretion of mutant protein and BM defects rather than collagen misfolding and proteotoxic stress. The BM defects lead to a pro-fibrotic state with increased fibrillar collagen deposition, cardiac stiffness, and ECM compositional defects. These are accompanied by altered regulation of pathways involved in sarcomere formation, sarcolemma stability and cardiomyocyte metabolism, establishing a molecular signature of COL4A1-related cardiac disease. Intriguingly, aspects of this molecular signature including cardiac metabolic pathways, regulation of cardiac muscle contraction and BM component expression, are shared with common cardiomyopathies such as coronary micro-embolism, and dilated, ischemic and hypertrophic obstructive cardiomyopathies. By defining the molecular and phenotypic cardiac components of Gould syndrome these data show that the BM is essential for maintaining systolic and diastolic function and that alterations to the BM leads to a fibrotic response. These data increase insight into the role of the basement membrane and collagen IV in cardiac biology, and highlights mechanisms shared between Gould syndrome and common adult cardiac disease.
| Item Type: | Articles |
| Additional Information: | This work was supported by the MRC [MR/R005567/1 (to T.V.A.)]; the BHF [PG/15/92/31813 (to T.V.A.)]; the Stroke Association [grant number 16VAD_04 (to T.V.A.)]; Heart Research U.K. [grant number RG 2664/17/20 (to T.V.A, F.Q. and E.B)]. M.C acknowledges MRC (MR/S005412)]; and the BBSRC [CASE DTP studentship to A.H.; BB/L024551/1) and Royal Society (RGS/R1/231400).BB/T001984/1 to J.S.). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Boland, Dr Erin and Van Agtmael, Professor Tom and Huethorst, Dr Eline and Quondamatteo, Prof Fabio and MacDonald, Dr Eilidh and Cantini, Dr Marco and Fuller, Professor Will and Walker, Dr Matthew and Robertson-Gray, Dr Olivia and Smith, Professor Godfrey and Loughrey, Professor Christopher and Salmeron-Sanchez, Professor Manuel |
| Authors: | Boland, E., Hoyle, A., Robertson-Gray, O., Fuller, W., Swift, J., Cantini, M., Walker, M., Huethorst, E., MacDonald, E., Loughrey, C., Salmeron-Sanchez, M., Smith, G. L., Quondamatteo, F., and Van Agtmael, T. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Science and Engineering > School of Engineering > Biomedical Engineering |
| Journal Name: | Matrix Biology |
| Publisher: | Elsevier |
| ISSN: | 0945-053X |
| ISSN (Online): | 1569-1802 |
| Published Online: | 12 September 2025 |
| Copyright Holders: | Copyright © 2025 The Author(s). |
| First Published: | First published in Matrix Biology 2025 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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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
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
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
Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutations
Tom Van Agtmael
RG 2664/17/20
SCMH - Cardiovascular & Metabolic Health
Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair
Marco Cantini
Medical Research Council (MRC)
MR/S005412/1
ENG - Biomedical Engineering
Harnessing viscoelasticity for regenerative medicine
Marco Cantini
RGS/R1/231400
ENG - Biomedical Engineering
Deposit and Record Details
| ID Code: | 366006 |
| Depositing User: | Mr Alastair Arthur |
| Datestamp: | 17 Sep 2025 10:59 |
| Last Modified: | 30 Sep 2025 07:29 |
| Date of acceptance: | 11 September 2025 |
| Date of first online publication: | 12 September 2025 |
| Date Deposited: | 17 September 2025 |
| Data Availability Statement: | Yes |
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