Morphological and morphometric changes in rat optic nerve microvessels in a glaucoma experimental model

Moreno, Mercedes; Ríos, M.C.; Alba, Carmen; Díaz, F.; Villena, Alicia; Figueroa-Ortiz, L.C.; García-Campos, J.M.

doi:10.1016/j.oftale.2014.10.008

Cited by 5 publications

(5 citation statements)

References 23 publications

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“…In parallel with IOP elevation, retinal vessel density decreases in concomitance with lacunarity increase, which reflects a non-uniform vessel organization. This is in keeping with previous findings in preclinical models demonstrating reduced density of retinal capillaries at the level of the optic nerve head as a result of acute IOP increase [21].…”

Section: Discussionsupporting

confidence: 93%

“…In fact, spontaneously occurring small fluctuations in IOP have been shown to generate chronic, low-grade ischemia-reperfusion injury, leading to blood vessel narrowing and reduced vessel density that progressively establish oxidative stress and trigger RGC loss [15]. Vasculature regression has been demonstrated in patients with diagnosed hypertensive glaucoma [16,17] and has been reported over a limited time window in glaucoma models soon after acute IOP elevation [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis

Amato

Cammalleri

Melecchi

et al. 2023

Cells

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Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often occur independent of IOP, indicating a multifactorial nature of glaucoma, with the likely contribution of glial and vascular function. The aim of the present study was to provide a comprehensive evaluation of the time course of neuro–glial–vascular changes associated with glaucoma progression. We used DBA/2J mice in the age range of 2–15 months as a spontaneous model of glaucoma with progressive IOP elevation and RGC loss typical of human open-angle glaucoma. We found that the onset of RGC degeneration at 10 months of age coincided with that of IOP elevation and vascular changes such as decreased density, increased lacunarity and decreased tight-junction protein zonula occludens (ZO)-1, while hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were already significantly upregulated at 6 months of age together with the onset of Müller cell gliosis. Astrocytes, however, underwent significant gliosis at 10 months. These results indicate that Müller cell activation occurs well before IOP elevation, with probable inflammatory consequences, and represents an early event in the glaucomatous process. Early upregulation of HIF-1α and VEGF is likely to contribute to blood retinal barrier failure, facilitating RGC loss. The different time courses of neuro–glial–vascular changes during glaucoma progression provide further insight into the nature of the disease and suggest potential targets for the development of efficient therapeutic intervention aside from IOP lowering.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis

Amato

Cammalleri

Melecchi

et al. 2023

Cells

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“…Puyang et al 49 found that OFF‐RGC types have the highest risks, and the OFF component of response in ON‐OFF cells to be more susceptible to optic nerve injury than ON. It is hypothesized that these findings are attributed to differences in the expression of calcium permeation receptors (such as pannexin‐1, P2X7, AMPA, and transient receptors, potential vanilloid receptors), 50‐54 blood supply of the plexiform layer, 55,56 and metabolic requirements in different RGC types 57,58 . However, vulnerability of RGC types and related mechanisms are not yet concrete, can could be basis for future research.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Huang

et al. 2021

FASEB j.

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Microglia activation and release of pro‐inflammatory cytokines have been closely linked to glaucoma. However, the mechanisms that initiate these pathways remain unclear. Here, we investigated the role of a pro‐inflammatory cytokine––osteopontin (OPN), in retinal microglia activation process along with the underlying mechanisms in glaucoma. A rat chronic ocular hypertension (COH) model was established presenting an increase in retinal OPN level and activation of microglia. Primary microglia cells were isolated and cultured under a pressure culture system showing heightened expressions of microglia‐derived OPN with changes in inflammatory factors (TNF‐α, IL‐1β, and IL‐6). OPN and OPN neutralizing antibody (Anti‐OPN) interventions were both applied systems for comparison, and cross‐referenced with OPN knockdown in vitro. JAK/STAT, NF‐κB, ERK1/2, and p38 MAPK, recognized as the primary signaling pathways related to microglia activation, were then screened on whether they can facilitate OPN to act on microglia and their impact on specific inhibitors. Thereafter, retrograde labeling of retinal ganglion cells (RGCs) and flash visual evoked potentials (F‐VEP) were used to investigate neuron protection in context of each blockade. Results suggest that OPN is able to enhance the proliferation and activation of retinal microglia in experimental glaucoma which may play a role in the glaucomatous optic neuropathy, and contribute to the eventual RGCs loss and vision function impairment. Such effect may be mediated through the regulation of p38 MAPK signaling pathway.

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“…94 Experimental glaucoma in rats showed reduced capillary volume, perimeter, diameter and density in regions of the optic nerve. 95 Similarly, DBA/2 J mice have reduced choroidal and retinal blood flow associated with increased IOP at nine months of age. 96 Given that OFF RGC dendrites are close to the intermediate capillary plexus one might expect that they are better perfused.…”

Section: Implications Of Vascular Perfusion In Rgc Dysfunctionmentioning

confidence: 99%

Potential mechanisms of retinal ganglion cell type‐specific vulnerability in glaucoma

Wang

Lee

Bui

et al. 2020

Clinical and Experimental Optometry

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Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type‐specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types – particularly OFF RGCs. Several mechanisms may contribute to type‐specific vulnerability, including differences in the expression of calcium‐permeable receptors (for example pannexin‐1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets.

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Morphological and morphometric changes in rat optic nerve microvessels in a glaucoma experimental model

Cited by 5 publications

References 23 publications

Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis

Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Potential mechanisms of retinal ganglion cell type‐specific vulnerability in glaucoma

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