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

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.青光眼发病风险近期被发现与绝经年龄存在关联。本研究旨在探究年龄与卵巢切除术（ovariectomy, OVX）所致的手术绝经，对眼球后部组织（包括巩膜与视神经乳头）基因表达的影响。我们同时分析了年龄与OVX对青光眼相关表达通路的影响，例如细胞外基质（extracellular matrix, ECM）重塑与转化生长因子-β（transforming growth factor-β, TGF-β）信号通路。为对比不同组织区域的此类变化，我们同时对视网膜进行了检测。本研究采用批量RNA测序技术，对幼年（3~4月龄）与中年（9~10月龄）的Long-Evans大鼠开展相关分析。研究结果显示，衰老与OVX均会显著改变上述眼组织的基因表达模式。具体而言，幼年大鼠接受OVX后，其ECM与TGF-β相关基因集出现显著富集，但该效应在中年大鼠中有所减弱，表明这一影响存在年龄依赖性。相较于延迟实施的OVX，早期OVX会显著激活ECM重塑与免疫应答相关通路。上述研究结果凸显了绝经时机在调控青光眼相关分子通路中的关键作用，提示早期绝经可能会提升个体罹患青光眼的风险。值得注意的是，在衰老与OVX处理的动物中，眼球后部组织与视网膜内的FOS基因均出现表达下调。FOS是细胞增殖与存活的核心调控因子，其表达失调可能在女性衰老与绝经过程中发挥重要作用。本研究强调，在理解与管控青光眼发病风险时，应纳入绝经等女性健康相关因素进行考量。