Glaucoma is a chronic, irreversible, and degenerative form of optic neuropathy (Gao et al., 2018). According to epidemiological studies, people with high myopia or related genetic factors are at high-risk for primary open-angle glaucoma (POAG) (Jonas et al., 2020). A 1 D increase in the degree of myopia is associated with a 20% increased risk of glaucoma, and the prevalence of POAG in high myopia people is 7.3 times higher than that in normal people (Ha et al., 2022; Wang et al., 2022).

Previous studies have reported possible reasons for why those with high myopia are more prone to POAG (Choquet et al., 2022). High myopia is an independent risk factor for POAG. First, thinner central corneal thickness can make intraocular pressure (IOP) more likely to be underestimated in patients with high myopia, masking early detection in those with POAG (Bullimore et al., 2021). Second, high myopia may weaken the resistance of ocular structures to ocular hypertension, such as through the deformation of ocular structures and the thinning of the sclera and lamina cribrosa caused by the elongation of the axial length (Li et al., 2022c; Oh et al., 2015). All these are structural factors contributing to susceptibility to POAG in individuals with high myopia. Diagnosing high myopic optic neuropathy in its early stages can be challenging, and determining the appropriate timing to initiate glaucoma treatment can also pose difficulties. Currently, we primarily employ imaging techniques to observe structural damage, such as thinning and pallor of neuroretinal rim, cupping of optic disk, cup-disk ratio, which may be similar to the damage observed in glaucoma (Zhang et al., 2024). There are few reports on the molecular mechanism of POAG pathogenesis in patients with high myopia.

The trabecular meshwork (TM) is located between Schwalbe's line and the scleral spur. It regulated IOP by adjusting aqueous humor outflow resistance, by altering trabecular cell morphology and remodeling the extracellular matrix (ECM) (Lakk and Križaj, 2021). The pathogenesis of POAG is characterized by the apoptosis of TM cells or a reduction in phagocytosis, resulting in an imbalance of aqueous humor circulation and an elevation in intraocular pressure (Saccà et al., 2016; Wright et al., 2016). Due to the variations in IOP with fluid movement and ciliary muscle pressure gradients, TM cells are continuously exposed to mechanical strain, leading to the expansion and compression of morphological structures (Wang et al., 2021b). Recent studies have reported that TM cells respond to mechanical strain by remodeling the ECM and cytoskeleton, altering gene expression, releasing cytokines, and regulating signal transduction (Xin et al., 2018; Zhou et al., 2020). Therefore, studying changes in TM cells might inform understanding of the mechanism underlying POAG pathogenesis in high myopia.

In this study, we demonstrated that stretch-induced mechanical stress caused cytoskeleton disruption, ECM remodeling and cellular apoptosis in the in vitro cultured primary rabbit TM cells and in human TM cell lines, which were reversed through the inhibition of YAP/TGFβ signaling. Meanwhile, we successfully verified the susceptibility of ocular hypertension to high myopia in the animal experiments and the protective effect of YAP/TGF-β signaling inhibition in TM pathogenesis induced by high myopia.