Interaction between 3 proteins may affect vEDS aortic rupture risk
Preventing aortic rupture is a key focus of vEDS research
An interaction between the proteins M2K6, p38, and ERK may substantially affect the risk of major bleeding problems in vascular Ehlers-Danlos syndrome (vEDS), and targeting them may help preserve blood vessel health, a study in mice suggests.
“The findings presented in this work suggest that pharmacologic strategies that can mimic the natural mechanism of protection … through modulation of M2K6/p38 … or ERK signaling pathways have a strong potential of reducing aortic rupture risk in vEDS,” the researchers wrote in the study, “Map2k6 is a potent genetic modifier of arterial rupture in vascular Ehlers-Danlos syndrome mice,” which was published in JCI Insights.
Mutations in the COL3A1 gene, which provides instructions to make a structural protein important for keeping blood vessels intact, are the cause of vEDS, which is marked by abnormally fragile blood vessels that increase the risk of aortic rupture, a potentially life-threatening complication where large blood vessels tear.
Preventing aortic rupture is a key focus of vEDS research, but an incomplete understanding of the molecular mechanisms that lead to such bleeding events has made progress challenging. To understand the biology of genetic diseases like vEDS, researchers often rely on mouse models. There are many different breeds or strains that may be used.
Proteins’ role in aortic rupture risk
This study began with the observation that, in one common strain of mice, mutations in COL3A1 lead to vEDS-like disease such that the mice often die of aortic rupture. But the same mutation almost never leads to aortic rupture in a different strain, suggesting the second mouse strain could carry some sort of genetic alteration that protected it against aortic ruptures even when the COL3A1Â gene is mutated.
The researchers looked for genetic variations that might be behind this protection from aortic rupture and zeroed in on variants in a gene called Map2k6, which provides instructions to make the protein M2K6. The scientists found that when the second strain of mice was engineered to lack Map2k6, they were more likely to have an aortic rupture if the COL3A1 gene was mutated.
The M2K6 protein is known to activate another protein called p38, which can deactivate a third protein called ERK.
The researchers showed that, if they blocked p38 in mice harboring a COL3A1 mutation, the mice were substantially more likely to have an aortic rupture, suggesting M2K6 protects against aortic rupture by activating p38 and deactivating ERK. Further tests showed that if the activity of ERK is blocked, the mice were protected from aortic rupture even when p38 was also blocked.
“These observations and the fact that increased risk of rupture due to p38 inhibition was rescued by … ERK inhibition, suggest that maladaptive integration between ERK and M2K6/p38 signaling contributes to the [development] of aortic rupture in vEDS animal models,” the researchers wrote.
Blocking ERK and/or activating M2K6 and P38 may help prevent life-threatening blood vessel destruction in vEDS patients, said the researchers, who noted that future studies are needed to better understand these mechanisms and to see if this molecular interaction functions in people the same way.
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