Abstract
Aortic dissection or rupture is a leading cause of mortality in vascular Ehlers-Danlos syndrome (VEDS), a disorder caused by mutations in the COL3A1 gene. Col3a1G938D/+ mice recapitulate features of VEDS, including high risk of aortic rupture. As in people with VEDS, aortic risk in this model accelerates at the onset of puberty, especially in males. We identify developmentally regulated gene programs associated with this vulnerability and that are targeted by treatments that mitigate aortic risk. Both genetic and pharmacological inhibition of the androgen receptor (AR) eliminated survival differences between sexes, while treatment with a dual AR and mineralocorticoid receptor (MR) antagonist provided near-complete and durable protection in both sexes. Pathways targeted by dual AR/MR inhibition, including those related to extracellular matrix (ECM) organization and cell-ECM interactions, largely overlapped with those also modulated by isolated MR antagonism. Selective targeting of MR signaling emerged as an effective therapeutic strategy in both sexes that avoids sexual side effects in males.
Authors
Emily E. Juzwiak, Caitlin J. Bowen, Rhiannon Edwards, Leda Restrepo, Serena Lee, Cassie A. Parks, Anthony Zeng, Maya M. Black, Oscar E. Reyes Gaido, Emily E. Bramel, Dustin T. Shigaki, Michael A. Beer, Chiara Bellini, Harry C. Dietz, Elena Gallo MacFarlane
Figure 4
AR/MR inhibition upregulates transcripts promoting ECM deposition and aerobic respiration, and downregulates transcripts related to Rho/Rac signaling and alternative mRNA splicing in multiple cell-types.
