Myopia's Influence on the Retinal Neurovascular Unit and its Implications in Glaucoma

Abstract

"Myopia is an increasingly common refractive error that not only causes distance vision blur, but also poses greater risks of developing ocular pathologies such as choroidal neovascularization, retinal detachments, glaucoma, and various maculopathies1, 2. Myopia prevalence is projected to increase from 28% in 2010 to almost 50% by 2050, and affect almost 5 billion people around the world3, 4. The global myopia epidemic is impossible to deny or ignore, with myopic maculopathies the primary cause of irreversible vision loss worldwide3. Glaucoma is a multifactorial eye disease characterized by irreversible optic neuropathy, progressive visual field deficits, and occasionally intraocular pressure (IOP) elevation; it is the second leading cause of blindness worldwide, and is estimated to affect over 120 million people by the year 20405. There is strong evidence confirming a relationship between myopia and glaucoma, and that myopic patients are more susceptible to glaucomatous degeneration. However, the mechanisms fundamental to this association remain unknown. There exist no early diagnostic markers for preventing myopia-associated glaucomatous onset and development1, 2, which can cause irrevocable structural and functional deficits, subsequently increasing vulnerability of the retina to glaucomatous degeneration. Through the work completed in this thesis, an assessment of components of the retinal neurovascular unit was performed to elucidate the effect of sustained myopia in an experimental non-human primate (NHP) model, and how myopia predisposes the retina to glaucomatous damage due to the effects of myopic eye growth and stretch on the inner retina. Myopia was induced in marmosets using soft single vision contact lens wear of varying refractive errors, while glaucoma was induced via intracameral injection of microbeads, causing angle occlusion and IOP elevation. Successful marmoset models of myopia, glaucoma, and myopic glaucoma were generated. During treatment, measurements of individual retinal layer thicknesses, axial length, and refractive error were gathered, and the density and distribution of retinal ganglion cells, astrocytes, and vasculature via immunohistochemistry (IHC), retinal layer thicknesses via optical coherence tomography (OCT), and functional assessment of cell function via electroretinography (ERG) were performed. Aim 1 investigated the effect of myopia on the retinal vascular template, astrocyte template, and retinal nerve fiber layer (RNFL) thickness in 6-month-old marmosets induced with myopia for four months. The analysis revealed an increase in pan-retinal string vessels and a decrease in peripheral vascular branch points, a decrease in Sox9+ astrocyte density, and increased glial fibrillary acidic protein (GFAP) glial reactivity in myopic eyes compared to age-matched controls. The RNFL was also thinner in myopic eyes compared to age-matched controls, and the relationship between astrocyte density and RNFL thickness known to exist in primates was present in controls, but not in myopic eyes. Aim 2 explored the effect of sustained defocus and aging on the retinal microvascular template of marmosets induced with myopia for four months compared to marmosets induced with myopia for ten months and age-matched controls. The analysis revealed an increased number of string vessels in all four vascular plexi and increased vascular branch points in the parafoveal retina but decreased in the peripapillary and peripheral retinas with myopia progression. Aim 3 examined the effect of sustained myopic eye growth on astrocyte cellular distribution, and its association with inner retinal layer thicknesses in marmosets induced with myopia for 4 months compared to marmosets induced with myopia for 10 months and age-matched controls. Myopic marmosets induced for 10 months experienced exacerbated pan-retinal decreased astrocyte density and increased GFAP-immunopositive spatial coverage, similar RNFL thinning but greater"