Hormone blocker reduces ruptured blood vessel risk in VEDS mouse study
Researchers found that treated animals with disorder had higher survival rates
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Blocking certain steroid hormone signaling helped reduce the risk of life-threatening blood vessel rupture in a mouse model of vascular Ehlers-Danlos syndrome (VEDS), according to a new study.
Unexpected tears in the aorta, the largest blood vessel in the body, are a major concern in VEDS. Using a mouse model, researchers tested whether blocking mineralocorticoid receptors (MRs), a part of steroid hormone pathways, affected this risk. They found that treated VEDS mice had higher survival rates than untreated mice.
“These data indicate MR signaling is a targetable pathway for aortic risk modulation in VEDS, with important translational implications,” researchers wrote.
The study, “Steroid hormone antagonism affords vascular protection in a mouse model of vascular Ehlers-Danlos syndrome,” was published in JCI Insight.
Aortic rupture particularly common among young adult men with VEDS
Ehlers-Danlos syndrome, or EDS, is a group of genetic disorders affecting the connective tissues that provide structure to joints, skin, blood vessels, and other tissues and organs. VEDS, one of the most severe forms of EDS, results from mutations in genes that encode collagens, a group of structural proteins. Symptoms of VEDS include skin and blood vessel fragility.
This fragility increases the risk of aortic rupture and internal bleeding. While sudden aortic rupture is a concern for anyone with VEDS, it is particularly common among young adult men. The reasons for these sex differences aren’t entirely clear, but they may be related to androgens, a group of sex hormones that includes testosterone.
“Although antihypertensive [blood pressure-lowering] agents show modest effectiveness in some clinical trials, no disease-altering VEDS treatments currently exist,” the researchers wrote.
They investigated potential therapies, along with the origins of sex differences in aortic rupture, using a mouse model of VEDS. Similar to humans, male VEDS mice are more likely to experience ruptures than females.
AR blockers increased 60-day survival rate
First, the team tested the hypothesis that androgens contribute to the heightened risk of aortic rupture among males. They used two methods — genetic engineering and medication — to reduce androgen signaling.
In male VEDS mice, genetic engineering increased survival at 60 days of age, corresponding to the end of adolescence, from 40% to 84%. Similarly, bicalutamide, an androgen receptor (AR inhibitor, increased 60-day survival from 53% to 74% relative to untreated controls. Neither strategy improved survival in female VEDS mice, supporting the theory that these hormones play a role in sex-specific risks of aortic rupture.
“These data indicated that while AR [blocking] protects males, residual risk persists in VEDS mice of both sexes, suggesting the existence of additional AR-independent modulators of aortic rupture risk,” the researchers wrote.
Bicalutamide, sold as Casodex and generics, has U.S. approval as a treatment for prostate cancer. However, it can cause side effects such as breast enlargement and erectile dysfunction. This may make it a less desirable therapy for people with VEDS.
Because of this, the team also tested a third method of AR blocking, using spironolactone (sold as Aldactone and others). Spironolactone also blocks receptors for mineralocorticoids, a group of steroid hormones that help regulate fluid balance in the body. Spironolactone has approval in the U.S. to help decrease blood pressure and treat certain types of heart failure.
Spironolactone increased 60-day survival to more than 90% in both male and female VEDS animals.
“The greater protection by spironolactone versus bicalutamide or genetic [engineering] led us to hypothesize that the mineralocorticoid receptor (MR), also inhibited by spironolactone, may be a VEDS therapeutic target,” the team wrote.
Our results suggest MR antagonism [blocking] warrants translational exploration as a VEDS therapeutic, particularly in males.
To probe this theory further, the researchers used Kerendia (finerenone), another approved medication that specifically inhibits MRs without affecting ARs. Kerendia increased survival at 60 days from 55% to 82% for males and from 65% to 89% for females.
This result suggests that both AR and MR signaling pathways are independently involved in aortic rupture risk. The AR pathway may help explain the difference between risk in males and females. MR pathways, conversely, seem to be involved in both sexes.
The researchers found that blocking either AR or MR increased levels of collagen and related proteins in certain aorta cells. This could help compensate for VEDS-related collagen deficiencies, the team noted. Blocking MR, but not AR, also increased elastin levels, a protein that helps give connective tissue its stretchy, elastic quality.
Alongside these protein-level changes, the scientists observed that the aortas of VEDS mice treated with spironolactone were more stretchy than those of untreated mice. This suggests that by increasing collagen and elastin, the medications increased the blood vessels’ capacity. This could help explain how they reduced the risk of aortic rupture.
“Our results suggest MR antagonism [blocking] warrants translational exploration as a VEDS therapeutic, particularly in males,” the team wrote. Blocking AR could also have survival benefits, per the findings in mice. However, because of the potential side effects, MR inhibitors may be preferable for future human use.
Future studies can continue investigating this hypothesis and exploring possible ways to safely translate these findings to humans.
