Potential treatment strategy for brain vascular disease
Blocking a specific immune cell response can reduce blood vessel lesions and blood clots in the disease Cerebral Cavernous Malformation, and potentially be used as a new treatment strategy. This is shown in a study from Uppsala University where the researchers have studied the mechanisms behind the disease in mice and in patient samples.
Favour Onyeogaziri and Peetra Magnusson (photo: David naylor, Mikael Wallerstedt)
Cerebral Cavernous Malformation (CCM) is a neurovascular disease where blood vessel lesions are formed which can cause hemorrhages, and in some cases, acute bleedings (stroke). With surgery being the only treatment strategy, understanding the molecular mechanisms of CCM is crucial for finding alternative therapeutic options for the disease.
Besides to blood vessel cells, several other cells types are involved in the formation of the blood vessel lesions. This includes the immune cell type neutrophils which become activated and are able to extrude structures called neutrophil extracellular traps (NETs). To study the role of NETs in CCM, the Uppsala researchers inhibited the formation of NETs in a mouse model of the disease.
“We treated the mice with the substance Cl-amidine that specifically reduces the neutrofils’ formation of NETs. This led to fewer vessel lesions which indicates that inhibition of NETs is a potential therapeutic strategy in CCM,” says Favour Onyeogaziri, doctoral student in Peetra Magnusson’s group at IGP and first author of the study.
One of the symptoms in CCM is blood coagulation and formation of blood clots that are not resolved, which is the most common scenario in normal conditions. In the CCM mice, the researchers observed the presence of what appeared to be chronic and unresolved clots. They showed an organised structure with new vessels within, indicating that the clots had been present for a prolonged time.
“It was previously known that the presence of NETs in blood clots can prevent the clots from being resolved. In our experiment we found fewer mice with organised clots in the group treated with Cl-amidine than in the control group,” says Peetra Magnusson, who led the study.
To investigate whether the presence of organised clots is relevant for CCM also in humans, the researchers examined brain tissue samples from CCM patients. In a large proportion of the patient samples, they found blood clots with an organised structure similar to the one they had detected in the mice.
“Our analyses suggested that these clots had new vessels inside and an increased deposition of immune cells. Since the clots can lead to inflammation and neurological damage, a therapy that removes the clots, for instance by inhibiting NETs, could be beneficial for CCM patients,” says Peetra Magnusson.
The study was performed in collaboration with researchers at the Department of Medical Biochemistry and Microbiology, Uppsala University, at SLU and in Finland and Italy. It has been published in the journal Nature Cardiovascular Research.