Steroid Hormone Dependent Pathogenesis in Vascular Ehlers-Danlos Syndrome

Vascular Ehlers-Danlos Syndrome (VEDS) is a genetic connective tissue disorder caused by heterozygous mutations in the COL3A1 gene encoding type III collagen which result in spontaneous rupture of the arteries, intestines, and gravid uterus. Aortic ruptures occur primarily in the descending thoracic aorta. Male VEDS patients experience a higher rate of catastrophic vascular events (dissections or ruptures) during puberty compared to females suggesting a role for androgens. Our Col3a1G938D/+ mouse model recapitulates the sexually dimorphic phenotype of spontaneous death due to aortic rupture in puberty. Our work with VEDS mice subjected to androgen receptor inhibition, through the use of a conditional allele for the androgen receptor (AR) to generate global Ar null mice or through the use of pharmacologic AR antagonism with bicalutamide, discovered that androgens drive sexual dimorphic survival. We also found a role for mineralocorticoid receptor signaling with the use of spironolactone, a dual AR and MR antagonist, and finerenone, a specific MR antagonist. Therefore, we employed single nucleus-RNAseq of the descending thoracic aorta to identify the molecular mechanism driving AR, MR, and dual AR/MR protection in VEDS male mice. We discovered AR or MR antagonism normalized expression of dysregulated transcripts in both VEDS endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In ECs, components of cell junctions and modulators of cell junction stability were dysregulated while transcripts encoding a contractile VSMC phenotype, integrin signaling, and focal adhesions were modulated in VSMCs.