Steroid hormone antagonism reduces the rate of aortic rupture and improves survival in a mouse model of Vascular Ehlers-Danlos Syndrome

Vascular Ehlers-Danlos syndrome (VEDS) carries a high risk of vascular rupture. In the Col3a1G938D/+ mouse model, the rate of aortic rupture accelerates postnatally, especially in males, concurrently with the rise in androgens. Here we show that this vulnerability is associated with the postnatal transition of the aorta to a non-synthetic state, and that androgen receptor (AR ) antagonism partially reversed this shift, resulting in a non-physiological increase in the expression of extracellular matrix components. Both pharmacological and genetic AR antagonism improved survival in males, while dual AR and mineralocorticoid (MR) inhibition, or selective MR antagonism, reduced the risk of aortic rupture in both sexes. In all major aortic cell types, there was substantial overlap in the transcriptional alterations imposed by AR, MR and dual AR/MR inhibition, suggesting that both AR/MR antagonism and selective targeting of the MR are potential therapeutic strategies in this condition.