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University of Cambridge scientists identify potential drug target for major cause of stroke and vascular dementia





A potential drug target that could help prevent a major cause of stroke and vascular dementia has been identified by Cambridge scientists, after they grew small blood vessel-like models in a lab.

They showed how damage to the scaffolding that supports these vessels can cause them to leak - a key characteristic seen in cerebral small vessel disease (SVD).

Disease brain endothelial cells stained for tight junction protein, occluding (red) and DAPI (nuclei, blue). Image: Alessandra Granata/University of Cambridge
Disease brain endothelial cells stained for tight junction protein, occluding (red) and DAPI (nuclei, blue). Image: Alessandra Granata/University of Cambridge

This condition, where blood leaks out of the vessels and into the brain, is a leading cause of age-related cognitive decline, contributes to 45 per cent of dementia cases worldwide and is responsible for 20 per cent of ischemic strokes. This is the most common type of stroke, where a blood clot prevents the flow of blood and oxygen to the brain.

Dr Alessandra Granata from the Department of Clinical Neurosciences at the University of Cambridge, who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease.

“Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”

Most SVD cases are associated with conditions such as hypertension and type 2 diabetes, and typically affect middle-aged people, but there rare, inherited forms of the disease that can strike younger people, often in their mid-thirties. Both forms share similar characteristics.

Disease mural cells stained for calponin (mural cells marker, green), collagen IV (magenta) and DAPI (nuclei, blue). Image: Alessandra Granata/University of Cambridge
Disease mural cells stained for calponin (mural cells marker, green), collagen IV (magenta) and DAPI (nuclei, blue). Image: Alessandra Granata/University of Cambridge

Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge took cells taken from skin biopsies of patients with one of the rare forms of SVD, caused by a mutation in a gene called COL4, and reprogrammed them to create induced pluripotent stem cells, which can develop into almost any type of cell within the body.

These stem cells were used to generate cells of the brain blood vessels and create a model of the disease to mimic the defects seen in patients’ brain vessels.

The COL4 gene is important for the health of a type of scaffolding, known as an extracellular matrix, around which our blood vessels are built.

But in the disease model, the team found this extracellular matrix was disrupted, particularly at ‘tight junctions’ that ‘zip’ cells together.

This led to the small blood vessels becoming leaky.

The scientists identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. While they usually play an important role in maintaining the extracellular matrix, when too many are produced, they can damage the structure.

But they were able to reverse the damage and stop the leakage by treating the blood vessels with an antibiotic and with an anti-cancer drug, both of which inhibit MMPs..

Metalloproteinases (MMPs) can play a key role in the disruption of the extracellular matrix that leads to leaky small blood vessels. Graphic: University of Cambridge
Metalloproteinases (MMPs) can play a key role in the disruption of the extracellular matrix that leads to leaky small blood vessels. Graphic: University of Cambridge

Dr Granata said: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”

The study, published in Stem Cell Reports, was funded by the Stroke Association, British Heart Foundation and Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.



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