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Ovariectomy Drives Increase an ECM Transcription Signature in the Posterior Eye and Retina

ABSTRACT: The risk of developing glaucoma has recently been associated with the age of menopause. This study examines how age and surgical menopause via ovariectomy (OVX) impact gene expression in the posterior eye, including the sclera and optic nerve head. We examined how age and OVX impacted expression pathways linked to glaucoma, such as extracellular matrix (ECM) remodeling and TGF-β signaling. To compare these changes across different tissue regions, we also examined the retina. Using bulk RNA sequencing, we analyzed these changes in young (3-4 months) and middle-aged (9-10 months) Long-Evans rats. Our results demonstrate that both aging and OVX significantly alter gene expression in these ocular tissues. Specifically, OVX in young rats led to significant enrichment of ECM and TGF-β gene sets, while these effects were diminished in middle-aged rats, indicating an age-dependent influence. Early OVX triggered significantly enriched ECM remodeling and immune responses compared to later OVX. These findings underscore the critical role of menopause timing in modulating molecular pathways associated with glaucoma, suggesting that early menopause may heighten the risk of developing this condition. Notably, FOS was downregulated in the posterior eye and retina in aging and OVX animals. FOS is a major regulator of cell proliferation and survival, and its dysregulation may play an important role in aging and menopause for women. This study highlights the importance of considering women's health factors, such as menopause, in understanding and managing glaucoma risk.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE272170 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:Despite an abundance of evidence to the contrary from animal studies, large clinical trials on humans have shown that estrogen administered to post-menopausal women increases the risk of cardiovascular disease. However, timing may be everything, as estrogen is often administered immediately after ovariectomy (ovx) in animal studies, while estrogen administration in human studies occurred many years post-menopause. This study investigates the discrepancy by administering 17ß-estradiol (E2) in a slow-release capsule to Norway Brown rats both immediately following ovx and 9 weeks post-ovx (Late), and studying differences in gene expression between these 2 groups as compared to age-matched ovx and sham operated animals. Two different types of microarray were used to analyze the left ventricles from these groups: an Affymetrix array (2 samples/group, each sample contained total RNAs pooled from 3 rats) and an Inflammatory Cytokines and Receptors PCR array (N=4 /group). Key genes were analyzed by western blotting. Ovx without replacement led to an increase in caspase 3, caspase 9, calpain 2, MMP9, and TNFα. Caspase 6, STAT3, and CD11b increased in the Late group, while TIMP2, MMP14, and collagen I α1 were decreased. MADD and fibronectin were increased in both Ovx and Late. TNFα protein levels increased with Late replacement. Many of these changes were prevented by early E2 replacement. These findings suggest that increased TNFα may be involved in some of the deleterious effects of delayed E2 administration seen in human studies. The rats were randomly assigned to four groups: Sham, Ovx, Early estrogen group, and Late estrogen group. The Sham rats were anesthetized, had their body cavities opened and then immediately closed with no tissue removal; the Ovx group underwent ovariectomy. The Early estrogen group after ovariectomy had a 0.5 mg 17-β estradiol 90-day slow release pellet (Innovative Research of America, Sarasota, FL) implanted subcutaneously in the back of the neck at the time of surgery. The Late estrogen group underwent ovariectomy and had a subcutaneous estrogen pellet placed, as above, at 9 weeks post-ovx. RNA target was prepared according to the instructions of the manufacturer (Affymetrix). For each RNA sample, good-quality total RNA from three rat hearts were pooled together in equal amounts and used to synthesize double-strand cDNA using a one-cycle cDNA synthesis kit (Affymetrix, P/N 900431). This approach allows repetitive analysis of all groups by the array in a group representative and cost effective manner, and has been used effectively by other investigators. Two pooled RNA samples were prepared for each group, and all the RNA samples were proceeded with Affymetrix expression chip analysis.

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Ovariectomy Drives Increase an ECM Transcription Signature in the Posterior Eye and Retina

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