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14th August 2023
A potential therapeutic target underlying the cause of reduced cerebral blood flow to the brain that results in vascular dementia has been recently discovered by researchers at the University of Manchester.
Published in the journal Proceedings of the National Academy of Sciences, the study, which was carried out in mice, reveals that hypertension disrupts signalling within artery cells in the brain and leads to vascular dementia. To date, there is limited understanding of the cellular and molecular mechanisms by which elevated blood pressures give rise to changes in brain arteries.
The researchers used a blood pressure high (BPH/2) mouse model of hypertension. They studied pial arteries, which regulate the flow of blood across the brain surface through myogenic constriction.
Normally, vasodilatation within these arteries occurs through activation of large-conductance, calcium-activated potassium channels on the plasma membrane by nearby localised calcium-release events – referred to calcium sparks – from the sarcoplasmic reticulum (SR) of vascular smooth muscle cells.
In contrast, vasoconstriction occurs as a result of diminished activity of the calcium-activated potassium channels.
The researchers found that in the hypertensive mice, there was increased constriction of pial arteries, which suggested that the calcium sparks occurred normally. However, they also observed that the distance between the SR and the potassium channels was increased. Consequently, the calcium sparks failed to activate the potassium channels, preventing the normal vasodilatory response.
The net effect was increased constriction of arteries, reducing cerebral blood flow and behavioural alterations in the mice that approximated to deficits observed in human vascular dementia patients, including executive dysfunction, apathy and memory loss.
Professor Adam Greenstein, a clinician scientist specialising in high blood pressure at the University of Manchester and one of the leaders of the research, said: ‘By uncovering how high blood pressure causes arteries in the brain to remain constricted, our research reveals a new avenue for drug discovery that may help to find the first treatment for vascular dementia. Allowing blood to return as normal to damaged areas of the brain will be crucial to stopping this devastating condition in its tracks.
‘Any drugs that are discovered to improve brain blood supply may also be able to open a new line of attack in treating Alzheimer’s disease, which causes very similar damage to blood vessels as vascular dementia. Drugs to restore healthy blood flow could make current treatments, which focus on removing harmful amyloid plaques in the brain, more effective.‘
Professor Sir Nilesh Samani, medical director at the British Heart Foundation, which funded the research, added: ‘Vascular dementia affects around 150,000 people in the UK, and this number is going up. There are no treatments to slow or stop the disease, but we know that high blood pressure is an important risk factor. The incurable symptoms are hugely distressing for patients and those close to them.
‘This exciting research reveals a specific mechanism by which high blood pressure might increase the risk of vascular dementia. Pinpointing how arteries remain permanently narrowed in vascular dementia could lead to the development of new effective treatments, raising hope that there may soon be a way to prevent this illness from destroying more lives.‘