Scleral hypoxia is a target for myopia control

Abstract

Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1α (HIF-1α)-signaling pathway. Furthermore, experimental myopia selectively induced HIF-1α up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1α expression as well as the phosphorylation levels of eIF2α and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2α phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia.

Atropine Differentially Modulates ECM Production by Ocular Fibroblasts, and Its Ocular Surface Toxicity Is Blunted by Colostrum

“…Such remodeling of the sclera in myopia is associated with decreased amounts of collagen type 1 (the main component of its ECM), and treatment with atropine in several in vivo studies has been shown to increase the content of collagen-1 in sclera ECM. Another relevant correlate with myopia development is a thinning of the choroid and a decrease of blood perfusion of eye tissues [8,9].…”

<p>Pathogenesis and Prevention of Worsening Axial Elongation in Pathological Myopia</p>

“…18,19 A study by Wu et al reported that scleral hypoxia plays a pivotal role in myopia induced scleral remodeling. 30 The triggers for scleral hypoxia are multifold. The retina contains the highest consumption of oxygen in the body and has continuous light exposure, which is highly susceptible to generating Reactive Oxygen Species (ROS).…”

“…Wu et al postulated that hypoxia-induced myofibroblast trans-differentiation down-regulates type I collagen synthesis, which results in scleral structural changes, thus emphasizing the potential role of hypoxia in myopia. 30 Scleral architecture alterations with resultant staphyloma are detected using color fundus photography, ultrasonography, 2-dimensional Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), and more recently a 3-dimensional MRI. The new high-resolution 3D MRI with volume rendering techniques analyzes the entire shape of the eye to delineate the posterior staphyloma in highly myopic eyes.…”

“…146,147 In experimentally induced myopic animal models, Wu et al documented that the anti-hypoxic drugs down-regulated HIF-1α expression and the phosphorylation levels of eIF2α and mTOR to inhibit the development of form deprivation myopia, without affecting the normal ocular growth in guinea pigs. 30 The suppression of myopia in the animal models suggests the potential of these agents in the treatment of myopia in human eyes. The role of scleral hypoxia induced scleral ECM remodeling in the pathogenesis of myopia bears further investigation.…”

Reduction of Myopia Burden and Progression

“…Anti-hypoxic drugs such as salidroside and formononetin have shown antihypoxic effects to treat scleral hypoxia in myopia [53,54]. Scleral hypoxia, which is induced by Hypoxia-Inducible Factor-1α (HIF-1), triggers a signaling cascade for myofibroblast trans-differentiation leading to scleral extracellular collagenous matrix remodeling in progressing myopia [55]. Formononetin is known decrease HIF-1α, vascular endothelial growth factor (VEGF) and prolyl hydroxylase domain-2 (PHD-2), which are protective in hypoxia-induced retinal neovascularization [54].…”