Lab-grown blood vessels are providing new insight into how damage to the tiny vessels in the brain can cause them to leak, contributing to dementia and stroke.
Even better, this research has identified a drug target that could plug these leaks and potentially reduce a person’s risk of brain-damaging blood vessel leaks.
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Antibiotic and anti-cancer drugs that inhibit a class of biochemical called metalloproteinases (MMPs) reversed damage occurring in the lab-grown blood vessels and stopped leakages.
“These particular drugs come with potentially significant side effects, so wouldn’t in themselves be viable to treat small vessel disease,” said study author Dr. Alessandra Granata, of the department of clinical neurosciences at the University of Cambridge in England.
“But they show that in theory, targeting MMPs could stop the disease,” Granata added in a university news release. “Our model could be scaled up relatively easily to test the viability of future potential drugs.”
Cerebral small vessel disease (SVD) contributes to almost half (45%) of dementia cases worldwide, researchers said in background notes.
It is also responsible for about one in five (20%) ischemic strokes, which occur when a blood clot blocks blood flow to the brain. Most cases are associated with chronic illnesses like high blood pressure and type 2 diabetes, and they typically affect people in middle age.
For this study, Cambridge researchers gathered cells from skin biopsies of patients with a rare genetic form of small vessel disease, which is caused by a mutation in a gene called COL4.
The research team reprogrammed the skin cells into stem cells, which have the capacity to develop into nearly any type of cell within the body.
They then used these stem cells to generate brain blood vessels, creating a model that mimics the defects seen in patients with small vessel disease.
“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,” Granata explained.
“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,” she noted. “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.”
Blood vessels are built around a scaffolding called an extracellular matrix, which lines and supports the tiny vessels in the brain. The COL4 gene is important for the health of this matrix.
Researchers found that disruption of this matrix leads to small blood vessels becoming leaky.
Further, researchers identified MMPs as playing a key role in this damage. MMPs typically are important for maintaining the matrix, but if too many are produced they can damage the structure.
The new study was published Nov. 16 in the journal Stem Cell Reports.