Androgen and Mineralocorticoid Receptor Signaling Contribute to Pubertal Vascular Rupture in Vascular Ehlers-Danlos Syndrome (VEDS) mice

Description of Background: Males with VEDS are at a high risk of spontaneous death due to arterial rupture during puberty compared to females. Our VEDS mouse model (Col3a1G938D/+) recapitulates this sexually dimorphic vulnerability, with 51% vs. 63% survival of males vs. females at 60 days of age, respectively.

Methods: Given the male bias of death at puberty, we hypothesized that vascular rupture involved androgen-dependent perturbation of cellular function. We treated Col3a1G938D/+ mice with the selective AR antagonist (ARa) bicalutamide or the dual ARa and mineralocorticoid receptor antagonist (MRa) spironolactone from weaning until 60 days of age. We also initiated treatment of Col3a1G938D/+ mice with spironolactone after the completion of puberty. As a control, we treated Col3a1G938D/+ mice with the selective MRa finerenone from weaning until 60 days of age. We also induced the null state for the AR in Col3a1G938D/+ mice using a conditional (floxed) allele for the Ar gene in combination with an allele that globally express Cre recombinase.

Results: We observed that male Col3a1G938D/+ AR null mice have improved survival compared to untreated Col3a1G938D/+ mice at 60 days (80% vs. 51%), a protective performance similar to treatment with bicalutamide (69% survival). Immunoblot analysis of aortic lysates showed that AR blockade, either chemical or genetic, normalizes activation of the PKC/ERK axis. These data suggest that AR signaling contributes to vascular disease in Col3a1G938D/+ mice. Notably, male Col3a1G938D/+ mice treated with the dual ARa/MRa spironolactone showed the best performance (92% survival at 60 days). Interestingly, use of the selective MRa finerenone afforded intermediate protection (83% male survival at 60 days). Identical trends were observed in female Col3a1G938D/+ mice. Postpubertal treatment with spironolactone afforded essentially complete protection in both sexes.

Conclusion: These data document that pubertal vascular catastrophe in Col3a1G938D/+ mice is dependent on both AR and MR signaling with dramatic protection afforded by dual antagonism. There is therapeutic potential for isolated MR antagonism that will maintain normal sexual development in adolescent males.

Learning Objective: Upon completion, participant will be able to: articulate risk factors for pubertal vascular rupture in Vascular Ehlers-Danlos Syndrome; understand the role of androgens in disease and identify much needed therapeutics for VEDS.