Abstract
Purpose :
The age of menopause is a potentially important risk factor for glaucoma (Vajaranant et al. 2012), and scleral biomechanics play a major role in glaucomatous insult to the optic nerve head. Here, we investigate the impact of age and surgically induced menopause (ovariectomy [OVX]) on scleral gene expression.
Methods :
RNA was isolated from scleral tissues of young (3-4 months) and middle-aged (9-10 months) Brown Norway rats. In both age groups, rats underwent OVX or sham surgery (N=6 rats/group) and tissues were collected 8 weeks later for bulk RNA sequencing. Gene set variation analysis (GSVA) was used together with C2 canonical signaling gene sets (Broad Institute) to identify significantly enriched gene sets between experimental groups.
Results :
Gene sets related to extracellular matrix (ECM) remodeling, collagen synthesis and degradation, and matrix metalloproteinases (MMPs) had lower enrichment scores in aged sham animals vs. young sham. The top differentially expressed genes included ECM components Col1A1 and ELN, which decreased in expression levels with age (FDR adjust p<0.05). However, ECM-related gene sets had higher enrichment scores in young OVX animals compared to young sham, i.e., opposite to the effect of aging. Greater enrichment was observed with OVX in gene sets related to collagen synthesis and degradation as well as cell-ECM interactions. At the gene level, metallopeptidase ADAMTS1 was one of the top differentially expressed genes (increased by OVX; FDR adjust p<0.05). Gene sets related to TGF-b signaling and epithelial-to-mesenchymal transition were differentially expressed with both age and OVX, suggesting that TGF-b is involved in the observed changes in matrix remodeling gene expression.
Conclusions :
Our results suggest that aging and surgical menopause have opposite effects on scleral ECM turnover and TGF-b signaling. In particular, animals that underwent ovariectomy showed greater enrichment of ECM-related genes compared to aged-matched controls, while similar gene sets had decreased enrichment scores with age. Further research is needed to understand how these changes in transcription of ECM remodeling genes relate to changes in ocular compliance and outflow facility with age and ovariectomy (Feola et al. 2020).
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.