Endoplasmic reticulum stress may underlie vEDS complications: Study
Researchers say findings could explain range of symptom severity
Stress in a cell compartment called the endoplasmic reticulum (ER) may cause irregularities in collagen fibrils that underlie the serious blood vessel-related symptoms of vascular Ehlers-Danlos syndrome (vEDS), according to a recent study.
Patients who had more irregular collagen fibrils — major structural units of cells — tended to have high levels of ER stress and were more likely to experience symptoms like blood vessel tears and ruptures than patients with less irregular fibrils.
“Our results provide several clues to elucidate the novel pathophysiology [disease mechanisms] of vEDS,” the researchers wrote, noting that the findings could help explain why vEDS patients experience a wide range of symptom severity.
Importance of type III collagen
Type III collagen is important for giving tissues structural integrity, thus, vEDS patients experience fragile connective tissues. In addition to common EDS symptoms, including overly mobile joints and stretchy skin, vEDS patients also have fragile blood vessels, leading to serious complications like vessel ruptures and tears that cause internal bleeds.
Still, the symptoms of vEDS are highly variable, even between family members who have the same disease-causing mutation.
It isn’t clear what the underlying factors for this variability are, but evidence suggests that it is not just collagen levels that contribute. Existing research indicates that ER stress leading to irregular collagen fibril size could be a potential factor, according to authors.
Collagen fibrils are formed by tightly wound collagen molecules and other proteins. They have been previously found to be irregularly sized in vEDS patients.
The ER is the major site of cellular protein production and transport. Under conditions of cellular stress or damage, abnormal proteins accumulate in the ER and cause it to expand, or dilate. This can have significant consequences for normal protein transport throughout the cell. ER dilation has been observed in skin cells from vEDS patients.
In the recent study, scientists in Japan aimed to more closely evaluate these factors in vEDS. They obtained skin samples from 27 vEDS patients at the time of diagnosis, five healthy people (healthy control), and 48 people who were tested for a suspected hereditary connective tissue disease but were not found to have vEDS (disease-negative control).
Using a technique called electron microscopy, the scientists found that vEDS patients had irregularly sized collagen fibrils with more variation relative to both control groups, but this did not correlate with levels of a precursor molecule of type III collagen or type of COL3A1 mutation.
Still, a subset of seven vEDS patients exhibited low collagen fibril irregularity relative to the other 20 patients. These patients were significantly younger and less likely to have serious complications such as an artery tear or rupture.
Moreover, they exhibited only mild or no ER dilation in skin cells, whereas those with more irregular fibrils had high levels of dilation, indicating that more ER stress accompanies irregular fibrils.
Activity of the ATF6 gene, a marker of ER stress, was significantly increased in patients with more irregular collagen fibrils and another marker called COMP had lower activity in these patients.
Treatment with Edsivo
The scientists also highlighted the case of one particular vEDS patient who had been treated with Edsivo (celiprolol), a blood pressure medication now being developed by Acer Therapeutics for vEDS. With three years of treatment, levels of the type III collagen precursor molecule didn’t change, but collagen fibril irregularity was normalized and ER dilation was eliminated. The patient did not experience serious blood vessel complications for three years.
Taken together, the researchers believe the findings indicate that high ER stress could affect protein composition of collagen fibrils, leading to irregularities that compromise structural integrity of blood vessels. That could explain why patients with more ER stress tended to have higher rates of serious disease manifestations.
“Future studies are warranted to clarify the improvement in collagen fibril formation, whether ER stress could become a new potential therapeutic target to reduce the risk of fatal complications … and whether monitoring of ER stress in skin tissue can contribute to the prediction of ER stress status in other important organs,” the team concluded.