The delivery of oxygen and nutrients across the body through blood flow is crucial to maintaining healthy organs and tissues. Disruption of the blood vessels leading to and within the brain is potentially fatal, and such neurovascular dysfunction forms a major component of neurodegenerative diseases like Alzheimer’s disease, vascular dementia, and stroke.

Another condition which is characterised by neurovascular dysfunction is brain arteriovenous malformations (bAVMs), a condition where blood vessels become entangled and/or poorly formed, and are particularly prone to rupture. The cellular mechanisms leading to bAVMs is relatively unknown with the primary focus of research centring on the endothelial cells which line the blood vessels.

Reduction In Pericytes

A multi-institute clinical research study has now investigated the role of the cells which surround the endothelium – called pericytes – through patient samples of bAVMs. This study found that a reduction in pericytes surrounding the damaged blood vessels was associated with the formation of bAVMs, associated vascular instability and increased risk of rupture.

This finding is interesting and correlates with other research into pericytes, which has shown the crucial role of pericytes to maintaining cerebral blood flow and the detrimental effects of pericyte dysfunction in different vascular dementias.

A notable disease example of this is with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a vascular dementia which is characterised by a hereditary genetic mutation in pericytes cells that leads to abnormal function and pericytes cell death which leads to cognitive decline and associated dementia.

Vessel Rupture

The researchers surgically removed bAVMs or control tissues from patients for subsequent staining of samples for cellular markers. This identified the reduced proportion of pericytes cells surrounding bAVMs, with significantly less pericytes marker staining in bAVM tissue compared to controls.

One of the major risks of bAVMs is the increased risk of vessel rupture, which can follow on from microhaemorrhages and lead to a potentially fatal and life changing stroke or intracerebral haemorrhage.

The researchers sought to investigate the effect of pericytes coverage on these microhaemorrhages by analysing the extent of pericyte coverage in correlation with the extent of microhaemorrhage in unruptured bAVM tissue. From this they established that a reduction in pericyte coverage is associated with an increased amount of microhaemorrhages.

Neurovascular Function Importance

Further animal research is needed to dissect the specific cellular and molecular pathways that cause the associated poorer outcome from reductions in brain pericyte coverage. This is because, although the correlations found in this research are significant, the dissection of specific pathways may lead to the development of a therapeutic option that could increase the quality of life and peace of mind in patients.

The research shown here builds greatly on animal research which has shown qualitative differences in the pericyte population in bAVM tissue; through both providing a human sample of tissue and by quantifying the pericyte coverage in two separate markers.

The use of patient tissue holds a significant advantage to animal tissue as the animal brain – while useful – does not fully replicate the human brain, and can result in poor translation to human benefit due to this.

Overall, this research adds to the mass of data which highlight the importance of pericytes to neurovascular function. This has implications in the study of neurovascular diseases, but also in the modelling of vasculature where endothelial cells are commonly researched in isolation, which doesn’t replicate the key intercellular interactions between endothelial and pericyte cells of blood vessels.

Winkler EA, Birk H, Burkhardt JK, Chen X, Yue JK, Guo D, Rutledge WC, Lasker GF, Partow C, Tihan T, Chang EF, Su H, Kim H, Walcott BP, Lawton MT. Reductions in brain pericytes are associated with arteriovenous malformation vascular instability Journal of Neurosurgery. 2018 Jan 5. doi: 10.3171/2017.6.JNS17860

Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Mouse brain capillaries, SEM. Credit: Izzat Suffian, Houmam Kafa, David McCarthy & Khuloud T. Al-Jamal. CC BY

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