Effects of selective EP2 receptor agonist, omidenepag, on trabecular meshwork cells, Schlemm’s canal endothelial cells and ciliary muscle contraction

AbstractThis study investigated the effects of omidenepag (OMD), a novel selective EP2 receptor agonist, on human trabecular meshwork (HTM) cells, monkey Schlemm’s canal endothelial (SCE) cells, and porcine ciliary muscle (CM) to clarify the mechanism of intraocular pressure (IOP) reduction involving conventional outflow pathway. In HTM and SCE cells, the effects of OMD on transforming growth factor-β2 (TGF-β2)-induced changes were examined. The expression of actin cytoskeleton and extracellular matrix (ECM) proteins, myosin light chain (MLC) phosphorylation in HTM cells were evaluated using real-time quantitative PCR, immunocytochemistry, and western blotting. The expression of barrier-related proteins, ZO-1 and β-catenin, and permeability of SCE cells were evaluated using immunocytochemistry and transendothelial electrical resistance. The CM contraction was determined by contractibility assay. OMD significantly inhibited expression of TGF-β2 induced mRNA, protein, and MLC-phosphorylation on cytoskeletal and ECM remodeling in the HTM dose dependently. In SCE cells, OMD suppressed TGF-β2-induced expression of the barrier-related proteins and decreased SCE monolayer permeability. OMD at 3 µM significantly inhibited CM contraction, however, the effect was not significant at lower concentrations. IOP lowering effect of OMD through conventional outflow pathway is exerted by increasing outflow facilities with the modulation of TM cell fibrosis and SCE cell permeability.

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The effects of exosomes derived from trabecular meshwork cells on Schlemm’s canal endothelial cells

Scientific Reports ◽

10.1038/s41598-021-01450-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eri Takahashi ◽

Junji Saruwatari ◽

Tomokazu Fujimoto ◽

Yuki Tanoue ◽

Takaichi Fukuda ◽

...

Keyword(s):

Trabecular Meshwork ◽

Transforming Growth Factor ◽

Positive Staining ◽

Schlemm’S Canal ◽

Trabecular Meshwork Cells ◽

Schlemm's Canal ◽

Exosomal Mirnas ◽

Collagen Type 1 ◽

Outflow Pathway

AbstractTrabecular meshwork (TM) and Schlemm’s canal (SC) are the main structures within the conventional outflow pathway, and TM cells and SC endothelial (SCE) cells are essential for controlling intraocular pressure. To examine the interaction between TM cells and SCE cells, we investigated whether exosomes contribute to intercellular communication. Additionally, TM cells in glaucoma acquire mesenchymal characteristics in response to transforming growth factor (TGF)-β2 and extracellular matrix proteins such as collagen type 1 (Col-1); these changes result in increased resistance of aqueous outflow. In this study, we stimulated TM cells with TGF-β2 and Col-1 and characterized the exosomal miRNAs (exomiRs) released in response to each stimulus. Isolated exosomes were rich in miRNAs, with downregulated miR-23a-5p and upregulated miR-3942-5p and miR-7515 levels following Col-1 or TGF-β2 stimulation. Next, a miRNA-mRNA network under TGF-β2 stimulation was constructed. There were no connections among the 3 miRNAs and predicted genes under Col-1 stimulation. GO and KEGG analyses revealed that the identified miRNAs were associated with various signaling pathways, including the inflammatory response. Interestingly, SCE cells treated with miR-7515 mimic showed increased VEGFA, VEGFR2, PECAM, and Tie2 expression. Ultrastructures typical of exosomes and positive staining for exosomal markers were observed in human TM cells. Our data showed that TM cells may communicate with SCE cells via exomiRs and that miR-7515 may be important for SCE cell reprogramming.

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Dynamic Changes of Scleral Spur Length In Different Accommodation States

10.21203/rs.3.rs-440328/v1 ◽

2021 ◽

Author(s):

Liugui Chen ◽

Wei Jin ◽

Xinlei Hao ◽

Xuejie Li ◽

Yiqiao Xing

Keyword(s):

Optical Coherence Tomography ◽

Trabecular Meshwork ◽

Roc Curves ◽

Ciliary Muscle ◽

Schlemm’S Canal ◽

Dynamic Changes ◽

Swept Source ◽

Schlemm's Canal ◽

Variable Distance ◽

Spur Length

Abstract This study aimed to evaluate the scleral spur length in response to different accommodation stimuli states, as well as the correlation with Schlemm’s canal and trabecular meshwork. 74 children were recruited for this study. The 0D, -4D, and − 8.0 D accommodation state was stimulated by looking at a variable distance optotype. The ciliary muscle, scleral spur, Schlemm’s canal, and trabecular meshwork were imaged by swept-source optical coherence tomography. The scleral spur length increased with accommodation stimulation (p < 0.05). Method I was 127.97 ± 20.32 µm, 138.29 ± 20.11 µm, and 150.73 ± 21.75 µm at 0D, -4D and − 8D, respectively. Method II was 158.15 ± 19.97 µm, 168.47 ± 18.72 µm, and 179.79 ± 20.83 µm at 0D, -4D and − 8D, respectively. Method III was 221.56 ± 30.74 µm, 234.99 ± 30.11 µm, and 250.09 ± 29.87 µm at 0D, -4D and − 8D, respectively. Method III had the largest areas under ROC curves (0.798, 95% CI 0.721–0.875). Moreover, ciliary muscle 1, Schlemm’s canal, and trabecular meshwork length were significantly correlated with SSL (Method III) (p < 0.05). These findings suggest that the contractile ability and compliance of the scleral spur play an important role in maintaining the morphology of the SC. Moreover, the force of accommodation regulates the SC size by increasing the length of SS.

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Combined Circumferential Canaloplasty and Trabeculotomy Ab Interno with the OMNI Surgical System

Frontiers in Ophthalmology ◽

10.36879/fro.21.000106 ◽

2021 ◽

pp. 1-9

Keyword(s):

Intraocular Pressure ◽

Trabecular Meshwork ◽

New Technology ◽

Schlemm’S Canal ◽

Schlemm's Canal ◽

Surgical Device ◽

Outflow Pathway ◽

Consequent Increase ◽

Surgical System ◽

Ab Interno

In the normal eye the conventional outflow pathway is responsible for the majority of aqueous humor egress and plays a key role in the maintenance of healthy intraocular pressure. However, in the glaucomatous eye pathologic changes to the pathway in the trabecular meshwork, Schlemm’s canal, and collector channel ostia can introduce abnormal resistance to outflow with consequent increase in intraocular pressure. The OMNI Surgical System (Sight Sciences, Menlo Park, CA USA) is a relatively new surgical device and the only one that combines two ab interno minimally invasive treatments in a single procedure, canaloplasty and trabeculotomy. This new technology allows surgeons to address outflow resistance wherever it may be, both proximally (juxtacanalicular trabecular meshwork and inner wall of Schlemm’s canal), and distally (Schlemm’s canal and the collector channels). This review covers several recent clinical studies of the OMNI device with the aim of collating what is known and what remains to be learned.

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Angle and Nonpenetrating Glaucoma Surgery

Complications of Glaucoma Surgery ◽

10.1093/oso/9780195382365.003.0011 ◽

2013 ◽

Author(s):

Huijuan Wu ◽

Teresa C. Chen

Keyword(s):

Endothelial Cells ◽

Anterior Chamber ◽

Trabecular Meshwork ◽

Glaucoma Surgery ◽

Anterior Chamber Angle ◽

Schlemm’S Canal ◽

Schlemm's Canal ◽

Outflow Pathway ◽

Aqueous Outflow ◽

Chamber Angle

The outflow of aqueous via the anterior chamber angle is a constant process. The aqueous is formed by the ciliary processes and then passes through the pupil from the posterior chamber to the anterior chamber (Figure 2.1). About 83%–96% of the aqueous finally exits the eye into the anterior chamber angle via the trabecular meshwork—Schlemm’s canal—venous system (i.e., the conventional or canalicular outflow pathway). The other 5%–15% of aqueous outflow occurs via uveoscleral outflow (i.e., the unconventional or extracanalicular outflow pathway), with aqueous passing through the ciliary muscle and iris, then entering into the supraciliary and suprachoroidal spaces, and then finally exiting the eye through the sclera or along the penetrating nerves and vessels. Glaucoma is usually associated with aqueous outflow problems through a variety of mechanisms. For the developmental glaucomas, the improper development of the outflow structures is the main reason for high eye pressures. In the primary and secondary open-angle glaucomas, the theories to explain the diminished outflow facility are numerous. Possible etiologies are as follows: deposition of foreign material (such as pigment, red blood cells, glycosaminoglycans, extracellular lysosomes, plaque-like material, and proteins) into the trabecular meshwork (TM) and the wall of Schlemm’s canal (SC), loss of trabecular endothelial cells, structural changes of the inner wall of SC, and abnormal phagocytic activity of trabecular endothelial cells. In angle closure glaucoma, the peripheral iris closes the entrance to the TM by the anterior pulling mechanism or the posterior pushing mechanism, resulting in the direct blockage of conventional outflow. The goal of angle and nonpenetrating procedures is to restore aqueous outflow, thereby lowering intraocular pressure (IOP). Angle surgery restores outflow by re-opening the natural channels for aqueous outflow, and nonpenetrating glaucoma surgery creates an artificial external filtration site and partly restores the normal physiologic pathways. In 1936, Otto Barkan was the first to describe a surgical procedure that creates an internal incision into trabecular tissue under direct magnified view of the anterior chamber angle.

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The pressures in the episcleral veins, Schlemm's canal and the trabecular meshwork in monkeys: Effects of changes in intraocular pressure

Experimental Eye Research ◽

10.1016/s0014-4835(89)80060-0 ◽

1989 ◽

Vol 49 (4) ◽

pp. 645-663 ◽

Cited By ~ 82

Author(s):

Olav Mäepea ◽

Anders Bill

Keyword(s):

Intraocular Pressure ◽

Trabecular Meshwork ◽

Schlemm’S Canal ◽

Schlemm's Canal

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An imaged-based inverse finite element method to determine in-vivo mechanical properties of the human trabecular meshwork

Modeling and Artificial Intelligence in Ophthalmology ◽

10.35119/maio.v1i3.48 ◽

2017 ◽

Vol 1 (3) ◽

pp. 100-111

Author(s):

Anup D. Pant ◽

Larry Kagemann ◽

Joel S. Schuman ◽

Ian A. Sigal ◽

Rouzbeh Amini

Keyword(s):

Mechanical Properties ◽

Finite Element ◽

Shear Modulus ◽

Trabecular Meshwork ◽

Computational Simulation ◽

Optimization Technique ◽

Schlemm’S Canal ◽

Aqueous Humor Outflow ◽

Schlemm's Canal

Aim/Purpose: Previous studies have shown that the trabecular meshwork (TM) is mechanically stiffer in glaucomatous eyes as compared to normal eyes. It is believed that elevated TM stiffness increases resistance to the aqueous humor outflow, producing increased intraocular pressure (IOP).It would be advantageous to measure TM mechanical properties in vivo, as these properties are believed to play an important role in the pathophysiology of glaucoma and could be useful for identifying potential risk factors. The purpose of this study was to develop a method to estimate in-vivo TM mechanical properties using clinically available exams and computer simulations.Design: Inverse finite element simulationMethods: A finite element model of the TM was constructed from optical coherence tomography (OCT) images of a healthy volunteer before and during IOP elevation. An axisymmetric model of the TM was then constructed. Images of the TM at a baseline IOP level of 11, and elevated level of 23 mmHg were treated as the undeformed and deformed configurations, respectively. An inverse modeling technique was subsequently used to estimate the TM shear modulus (G). An optimization technique was used to find the shear modulus that minimized the difference between Schlemm’s canal area in the in-vivo images and simulations.Results: Upon completion of inverse finite element modeling, the simulated area of the Schlemm’s canal changed from 8,889 μm2 to 2,088 μm2, similar to the experimentally measured areal change of the canal (from 8,889 μm2 to 2,100 μm2). The calculated value of shear modulus was found to be 1.93 kPa, (implying an approximate Young’s modulus of 5.75 kPa), which is consistent with previous ex-vivo measurements.Conclusion: The combined imaging and computational simulation technique provides a unique approach to calculate the mechanical properties of the TM in vivo without any surgical intervention. Quantification of such mechanical properties will help us examine the mechanistic role of TM biomechanics in the regulation of IOP in healthy and glaucomatous eyes.

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Morphological changes in the trabecular meshwork and Schlemm’s canal after treatment with topical intraocular pressure-lowering agents

Scientific Reports ◽

10.1038/s41598-021-97746-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ji-Hye Park ◽

Hyun Woo Chung ◽

Eun Gyu Yoon ◽

Min Jung Ji ◽

Chungkwon Yoo ◽

...

Keyword(s):

Intraocular Pressure ◽

Trabecular Meshwork ◽

Morphological Changes ◽

Open Angle Glaucoma ◽

Anterior Segment ◽

Schlemm’S Canal ◽

Schlemm's Canal ◽

Before And After ◽

Treatment Naïve ◽

Aqueous Outflow

AbstractGlaucoma treatment is usually initiated with topical medication that lowers the intraocular pressure (IOP) by reducing the aqueous production, enhancing the aqueous outflow, or both. However, the effect of topical IOP-lowering medications on the microstructures of the aqueous outflow pathway are relatively unknown. In this retrospective, observational study, 56 treatment-naïve patients with primary open-angle glaucoma were enrolled. Images of the nasal and temporal corneoscleral limbus were obtained using anterior segment optical coherence tomography (AS-OCT). The conjunctival vessels and iris anatomy were used as landmarks to select the same limbal area scan, and the trabecular meshwork (TM) width, TM thickness, and Schlemm’s canal (SC) area were measured before and after using the IOP-lowering agents for 3 months. Among the 56 patients enrolled, 33 patients used prostaglandin (PG) analogues, and 23 patients used dorzolamide/timolol fixed combination (DTFC). After 3 months of DTFC usage, the TM width, TM thickness, and SC area did not show significant changes in either the nasal or temporal sectors. Conversely, after prostaglandin analog usage, the TM thickness significantly increased, and the SC area significantly decreased (all P < 0.01). These findings warrant a deeper investigation into their relationship to aqueous outflow through the conventional and unconventional outflow pathways after treatment with PG analogues.

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Schlemm's canal and trabecular meshwork morphology in high myopia

Ophthalmic and Physiological Optics ◽

10.1111/opo.12451 ◽

2018 ◽

Vol 38 (3) ◽

pp. 266-272 ◽

Cited By ~ 8

Author(s):

Zhiqi Chen ◽

Yinwei Song ◽

Mu Li ◽

Wei Chen ◽

Shiliang Liu ◽

...

Keyword(s):

Trabecular Meshwork ◽

High Myopia ◽

Schlemm’S Canal ◽

Schlemm's Canal

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Anterior Segment Optical Coherence Tomography Signs of Local Dilatation Effect of a Micro-Stent on Schlemm’s Canal

Nepalese Journal of Ophthalmology ◽

10.3126/nepjoph.v10i2.23030 ◽

2018 ◽

Vol 10 (2) ◽

pp. 184-187

Author(s):

Kevin Gillmann ◽

Giorgio Enrico Bravetti ◽

Kaweh Mansouri ◽

André Mermoud

Keyword(s):

Optical Coherence Tomography ◽

Trabecular Meshwork ◽

Anterior Segment ◽

Optical Coherence ◽

Schlemm’S Canal ◽

New Device ◽

Schlemm's Canal ◽

Canal Diameter ◽

Trabecular Bypass

Introduction: The iStent inject® (Glaukos Corporation, CA, USA) is a relatively new device designed to be implanted ab-interno through the trabecular meshwork. This is, to the best of our knowledge, the first in-vivo description of a trabecular bypass device visualised with anterior segment optical coherence tomography (AS-OCT), and report of its structural effect on Schlemm’s canal. Case Report: A 74 year-old female patient suffering from long-standing primary open-angle glaucoma and nuclear sclerosis underwent cataract surgery combined with the implantation of two iStent injects®. Surgery was uncomplicated and achieved intraocular pressure (-1 mmHg) and medication (-2 molecules) reduction at 6 months. Under AS-OCT (Spectralis OCT, Heidelberg Engineering AG, Germany) the stent appears as a 300 μm long hyper reflective hollow device within the trabecular meshwork. Approximately a third of it protruded into the anterior chamber. Profound OCT signal loss was notable within the shadow of the device. A second AS-OCT section 500 μm beside the microstent shows a markedly dilated Schlemm’s canal, with a major diameter of 390 μm. Discussions: This report confirms that AS-OCT is a suitable technique to assess microstent positioning, and provides a first report on the in-vivo appearance of a functioning stent. It also indicates that iStent injects® could have a tangible effect on adjacent portions of Schlemm’s canal with, in this case, a 220% increase in canal diameter compared to the observed average (122 μm). This suggests the IOP-lowering effect of trabecular bypass devices could rely on a dual mechanism involving Schlemm’s canal dilatation.

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