New Paper Released by Tom Van Agtmael
Published: 30 August 2024
Article Released in the Lancet
Collage IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage
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.
Summary
Evidence before this study. Cerebral small vessel disease (CSVD) causes most strokes due to brain bleeding (intracerebral haemorrhage, ICH) and is the major cause of dementia due to vascular disease accounting for ~50% of all dementia cases. The genesCOL4A1/COL4A2 encode a collagen IV protein that is a major component of the basement membrane, a specialized extracellular matrix structure, in blood vessels. Previous studies showed that mutations in these genes cause a rare genetic form of CSVD as part of COL4A1-Syndrome. In addition, for late-onset sporadic CSVD non-coding variants are a risk factor in 65% of the population, while rare coding variants also occur. However, the molecular mechanisms causing CSVD and of genetic variants inCOL4A1/COL4A2 remain obscure.
Added value of this study. We uncovered in mice that develop cSVD that collagen IV regulates the function of endothelial cells that control the vasodilation of small arteries. We also provide new insight into mechanisms of CSVD as our data surprisingly show that in early stages of CSVD increased vasodilation occurs due to endothelial hyperpolarization. This is accompanied by changes in the structure and biomechanics of blood vessels with reduced vascular stiffness and increased wall thickness. Importantly these changes represents an early CSVD disease stage that is present 8 months before the development of ICH. We also show this is due to reduced levels of the protein collagen IV in the acellular part of blood vessels, called a basement membrane. Importantly, this mechanism is supported by data from our analysis of brain tissue from people with sporadic CSVD. Analysis of cerebral blood vessels from patients who did not have rare coding COL4A1/COL4A2 variants indicates common non-coding risk variants act by reduced collagen IV levels and increased vascular wall thickness. This wall thickening also occurs in people with CSVD carrying rare coding COL4A1/COL4A2 variants, with data suggesting they act via secreting mutant protein, and thus represents a point where the mechanisms of these different genetic variants converge.
Implications of all the available evidence. These data create new insight into the regulation of vascular function and mechanisms of CSVD, the leading cause of vascular dementia. They establish that increased EDH vasodilation occurs in early stages of CSVD, driven by reduced extracellular collagen IV levels that can be due to rare coding or common non-coding COL4A1/COL4A2 variants and mutations. The novel finding of excessive EDH vasodilation via reduced extracellular collagen IV levels provides new targets for future treatment strategies.
First published: 30 August 2024