Scientists say lab-grown small blood vessels used in new disease models point to a theoretical potential treatment for a major cause of stroke and vascular dementia.
Cambridge University researchers used the models to show how damage to the scaffolding that supports the small blood vessels can cause them to leak, leading to disease. The team has identified a potential drug target to “plug” these leaks and prevent so-called small vessel disease (SVD) in the brain, in a study published in Stem Cell Reports.
SVD is a leading cause of age-related cognitive decline and contributes to up to 45% of dementia cases worldwide. It is also responsible for 20% of ischemic strokes.
“Despite the number of people affected worldwide by SVD, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease,” said Dr. Alessandra Granata from the department of clinical neurosciences at Cambridge, who led the study.
Most of what is known about the underlying causes comes from limited animal studies, say scientists.
“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,” Granata said.
The blood vessels are built around a type of scaffolding known as an extracellular matrix, a netlike structure that lines and supports the small blood vessels in the brain.
Cambridge University’s website reports how scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute used cells taken from skin biopsies of patients with a rare form of SVD, which is caused by a mutation in a gene called COL4. By reprogramming the skin cells, they were able to create induced pluripotent stem cells and used them to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.
In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called “tight junctions,” which “zip” cells together. This leads to the small blood vessels becoming leaky -- a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.
Cambridge University says the researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure. When the team treated the blood vessels with drugs that inhibit MMPs -- an antibiotic and anticancer drug -- they found that these reversed the damage and stopped the leakage.
Targeting ECM-related proteins, such as MMPs, may be a promising “potential therapeutic option,” the researchers concluded.
“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,” Granata said.
The study was funded by the Stroke Association, the British Heart Foundation, and the Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.