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Steroid Hormone Dependent Pathogenesis in Vascular Ehlers-Danlos Syndrome

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE288058 | GEO | 2026/03/17

REPOSITORIES: GEO

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Project description:Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene, which encodes type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency causes fragile soft connective tissues, with life-threatening arterial and organ ruptures. There are currently no targeted therapies available. Although disease results from COLLIII misfolding caused by triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we conducted a comprehensive transcriptome analysis using RNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum (ER) stress response, and compromised autophagy, which may significantly impact the molecular pathology. We reported the first comprehensive map of complex gene expression networks, which may provide significant molecular insights into intricate interactions within cellular signaling pathways. the current RNA-seq data not only confirm these initial findings but also provide convincing evidence that ineffective proteostasis, unbalanced ER homeostasis, and compromised autophagy could substantially impact the molecular pathology driving the disease. aken together, or findings suggest that the accumulation of these misfolded aggregates can impair critical cellular functions such as ER proteostasis, adaptative responses to counteract ER stress (UPR and ERAD pathways), autophagy, mTOR pathway, and lysosome function. Perturbation of these key biological processes can have an impact on a range of cell activities, including differentiation, proliferation, and apoptosis, all of which are associated with the pathophysiology of vEDS. This work was supported by Fondazione Telethon and the “Associazione con Giacomo contro vEDS”, (Grant number: GSA21F001, Seed Grant Fall 2021 vEDS) to Nicola Chiarelli.

Project description:Estrogen receptor (ER) positive breast cancers exist in a complex environment of steroid hormones and their cognate receptors. Receptors for estrogens, progestogens (PR), androgens (AR), glucocorticoids (GR) and mineralocorticoids (MR) are variably expressed in these hormone- sensitive breast cancers. Clinical translation of crosstalk among these receptors has been limited by an incomplete understanding of ER reprogramming by PR, GR, AR and MR (NR3C receptors). This study reports that each of the NR3C receptors reprograms ER chromatin binding to sites enriched for NR3C binding motifs and that hormonal co-treatment increases the likelihood of ER binding to estrogen response elements. A major overlap is observed among ER conserved sites, but not among ER sites that are lost or gained due to reprogramming by each of the NR3C receptors. This stability of ER genomic binding is reflected in the resulting transcriptomes, as there is significant overlap among genes whose expression is unaltered in response to joint hormonal interventions but not among genes whose expression is enhanced or opposed by an individual NR3C receptor. The addition of NR3C ligands can enhance or oppose estrogen-mediated induction and repression of gene transcription, resulting in net agonism or antagonism of ER-mediated actions at gene loci and of cellular pathways of interest. In addition to differential modulation of chromatin binding, differences in cofactor associations for ER, PR and GR likely contribute to the divergent functions of these receptors in breast cancer. Among the NR3C receptors, MR activation differentially reprograms ER chromatin binding and, in contrast to ligands for PR, GR or AR, the MR ligand aldosterone does not inhibit estrogen-induced cell proliferation or potentiate the anti-proliferative effect of tamoxifen in ER+ MCF7 cells. PR, GR, AR and MR may be functionally relevant in ER+ breast cancer because higher expression of these NR3C receptors; or genes whose estrogen-regulated expression is altered by each of these receptors is significantly associated with better overall and relapse-free survival. In summary, this study highlights the diverse yet overlapping activities of NR3C receptors in reprogramming ER signaling.

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Steroid Hormone Dependent Pathogenesis in Vascular Ehlers-Danlos Syndrome

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