scholarly journals VIP Stabilizes the Cytoskeleton of Schlemm’s Canal Endothelia via Reducing Caspase-3 Mediated ZO-1 Endolysosomal Degradation

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Xiaotong Lou ◽  
Qianxue Mou ◽  
Bowen Zhao ◽  
Jingqiu Huang ◽  
Ke Yao ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
Caspase 3 ◽  
Umbilical Vein ◽  
Outer Wall ◽  
Cell Junctions ◽  
Schlemm’S Canal ◽  
Hek 293 ◽  
Schlemm's Canal ◽  
Filtration Barrier ◽  
Outflow Pathway

Objectives. In glaucomatous eyes, the main aqueous humor (AH) outflow pathway is damaged by accumulated oxidative stress arising from the microenvironment, vascular dysregulation, and aging, which results in increased outflow resistance and ocular hypertension. Schlemm’s canal (SC) serves as the final filtration barrier of the main AH outflow pathway. The present study is aimed at investigating the possible regulation of vasoactive intestinal peptide (VIP) on the cytoskeleton by stabilizing ZO-1 in SC. Methods. Model of chronic ocular hypertension (COH) induced by episcleral venous cauterization was treated with topical VIP. The ultrastructure of junctions, ZO-1 levels, and permeability of the SC inner wall to FITC-dextran (70 kDa) were detected in the COH models. The F-actin distribution, F/G-actin ratio, and ZO-1 degradation pathway in human umbilical vein endothelial cells (HUVECs) and HEK 293 cells were investigated. Results. ZO-1 in the outer wall of the SC was less than that in the inner wall. COH elicited junction disruption, ZO-1 reduction, and increased permeability of the SC inner wall to FITC-dextran in rats. ZO-1 plays an essential role in maintaining the F/G-actin ratio and F-actin distribution. VIP treatment attenuated the downregulation of ZO-1 associated with COH or H2O2-induced oxidative damage. In H2O2-stimulated HUVECs, the caspase-3 inhibitor prevents ZO-1 disruption. Caspase-3 activation promoted endolysosomal degradation of ZO-1. Furthermore, a decrease in caspase-3 activation and cytoskeleton redistribution was demonstrated in VIP + H2O2-treated cells. The knockdown of ZO-1 or the overexpression of caspase-3 blocked the effect of VIP on the cytoskeleton. Conclusion. This study provides insights into the role of VIP in stabilizing the interaction between the actin cytoskeleton and cell junctions and may provide a promising targeted strategy for glaucoma treatment.

Complications Common to Nonpenetrating Surgeries

2013 ◽  
Author(s):  
Andrew C. Crichton
Keyword(s):  
Glaucoma Surgery ◽  
Outer Wall ◽  
Glaucoma Drainage Device ◽  
Deep Sclerectomy ◽  
Success Rates ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Descemet's Membrane ◽  
Descemet’S Membrane ◽  
Controlled Flow

Nonpenetrating glaucoma surgery encompasses techniques that involve a deep dissection to the level of Descemet’s membrane, allowing aqueous seepage. The major techniques covered by the term “nonpenetrating surgery” are deep sclerectomy with or without implant and viscocanalostomy. In large meta-analyses comparing nonpenetrating procedures to trabeculectomy, trabeculectomy resulted in lower intraocular pressures (IOP) but a higher risk of postoperative complications. Although nonpenetrating surgery is successful in lowering IOP, the amount of IOP lowering is typically not as low as can be achieved with trabeculectomy. Consequently, patient selection with regard to the target IOP is important in the decision of whether or not to perform a nonpenetrating procedure. The goal of nonpenetrating procedures is to lower IOP with fewer complications than are seen with trabeculectomy. The complications that can occur can be easily understood and predicted by an understanding of the techniques and modifications, as well as knowledge and mechanisms of the adjustments that can be used postoperatively to enhance success. After appropriate anesthetic, the techniques involve a deep dissection in the sclera to the limbus. In the case of deep sclerectomy, after the initial half-thickness flap is fashioned, a second deeper flap is created and excised. This dissection is taken to the level of Descemet’s membrane, allowing controlled flow of aqueous. A fine forceps may be used to strip the outer wall of Schlemm’s canal, further enhancing the flow. The space created by the excision can then be filled with an implant, such as collagen (AquaFlow™ Collagen Glaucoma Drainage Device; STAAR® Surgical Company, Monrovia, California) or hyaluronate (SK Gel®; Corneal Laboratories, Paris, France). For viscocanalostomy, Schlemm’s canal is identified and dilated by using viscoelastic. With deep sclerectomy, intraoperative or postoperative antimetabolites may be used to try to increase success rates by limiting the inflammatory response. Goniopuncture to the Descemet’s window is often required postoperatively (in up to 67% of cases) to enhance flow and lower IOP. The available evidence on complications of nonpenetrating glaucoma surgery is relatively sparse and may be challenging to interpret. Comparative studies between trabeculectomy and nonpenetrating surgery would seem to show fewer complications in the nonpenetrating group.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Natsuko Nakamura ◽  
Megumi Honjo ◽  
Reiko Yamagishi ◽  
Nozomi Igarashi ◽  
Rei Sakata ◽  
...  
Keyword(s):  
Trabecular Meshwork ◽  
Receptor Agonist ◽  
Ciliary Muscle ◽  
Cell Permeability ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Ep2 Receptor ◽  
Mlc Phosphorylation ◽  
Related Proteins ◽  
Outflow Pathway

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.

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

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.

Differential P1-purinergic modulation of human Schlemm's canal inner-wall cells

2005 ◽  
Vol 288 (4) ◽  
pp. C784-C794 ◽  
Author(s):  
Mike O. Karl ◽  
Johannes C. Fleischhauer ◽  
W. Daniel Stamer ◽  
Kim Peterson-Yantorno ◽  
Claire H. Mitchell ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Aqueous Humor ◽  
Adenosine Receptors ◽  
Outer Wall ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Adenosine Receptor Agonists ◽  
Schlemm's Canal ◽  
Aqueous Humor Flow

Intraocular pressure is directly dependent on aqueous humor flow into, and resistance to flow out of, the eye. Adenosine has complex effects on intraocular pressure. Stimulation of A1and A2Aadenosine receptors changes intraocular pressure oppositely, likely through opposing actions on the outflow of aqueous humor. While the cellular sites regulating outflow resistance are unknown, the cells lining the inner wall of Schlemm's canal (SC) are a likely regulatory site. We applied selective adenosine receptor agonists to SC cells in vitro to compare the responses to A1and A2Astimulation. Parallel studies were conducted with human inner-wall SC cells isolated by a novel enzyme-assisted technique and with cannula-derived mixed inner- and outer-wall SC cells. A1agonists increased whole cell currents of both inner-wall and cannula-derived SC cells. An A2Aagonist reduced currents most consistently in specifically inner-wall SC cells. Those currents were also increased by A2B, but not consistently affected by A3, stimulation. A1, A2A, and A3agonists all increased SC-cell intracellular Ca2+. The electrophysiological results are consistent with the possibility that inner-wall SC cells may mediate the previously reported modulatory effects of adenosine on outflow resistance. The results are also consistent with the presence of functional A2B, as well as A1, A2A, and A3adenosine receptors in SC cells.

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

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.

Angle and Nonpenetrating Glaucoma Surgery

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.

scholarly journals Pharmacological regulation of outflow resistance distal to Schlemm’s canal

2018 ◽  
Vol 315 (1) ◽  
pp. C44-C51 ◽  
Author(s):  
Fiona McDonnell ◽  
W. Michael Dismuke ◽  
Darryl R. Overby ◽  
W. Daniel Stamer
Keyword(s):  
Dynamic Range ◽  
Smooth Muscle Actin ◽  
Anterior Segment ◽  
Physiological Model ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Outflow Facility ◽  
Schlemm's Canal ◽  
Anterior Segments ◽  
Outflow Pathway

The trabecular meshwork (TM) and Schlemm’s canal generate the majority of outflow resistance; however, the distal regions of the conventional outflow pathway account for 25–50% of total resistance. Sections of distal vessels are surrounded by α-smooth muscle actin-containing cells, indicating that they may be vasoregulated. This study examined the effect of a potent vasodilator, nitric oxide (NO), and its physiological antagonist, endothelin-1 (ET-1), on the regulation of outflow resistance in the distal regions of the conventional outflow pathway. Using a physiological model of the conventional outflow pathway, human and porcine anterior segments were perfused in organ culture under constant flow conditions, while intrachamber pressure was continually monitored. For porcine anterior segments, a stable baseline outflow facility with TM intact was first achieved before anterior segments were removed and a trabeculotomy was performed. For human anterior segments, a trabeculotomy was immediately performed. In human anterior segments, 100 nM ET-1 significantly decreased distal outflow facility from 0.49 ± 0.26 to 0.31 ±  0.18 (mean ± SD) µl·min−1·mmHg, P < 0.01. Perfusion with 100 µM diethylenetriamine-NO in the presence of 1 nM ET-1 immediately reversed ET-1 effects, significantly increasing distal outflow facility to 0.54 ± 0.35 µl·min−1·mmHg, P = 0.01. Similar results were obtained in porcine anterior segment experiments. Therefore, data show a dynamic range of resistance generation by distal vessels in both the human and the porcine conventional outflow pathways. Interestingly, maximal contraction of vessels in the distal outflow tract of trabeculotomized eyes generated resistance very near physiological levels for both species having an intact TM.

scholarly journals Increased stiffness and flow resistance of the inner wall of Schlemm’s canal in glaucomatous human eyes

2019 ◽  
Vol 116 (52) ◽  
pp. 26555-26563 ◽  
Author(s):  
Amir Vahabikashi ◽  
Ariel Gelman ◽  
Biqin Dong ◽  
Lihua Gong ◽  
Elliott D. K. Cha ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
Flow Resistance ◽  
Tissue Stiffness ◽  
Schlemm’S Canal ◽  
Force Microscopy ◽  
Schlemm's Canal ◽  
Afm Indentation ◽  
Atomic Force ◽  
Tissue Surface ◽  
Human Eyes

The cause of the elevated outflow resistance and consequent ocular hypertension characteristic of glaucoma is unknown. To investigate possible causes for this flow resistance, we used atomic force microscopy (AFM) with 10-µm spherical tips to probe the stiffness of the inner wall of Schlemm’s canal as a function of distance from the tissue surface in normal and glaucomatous postmortem human eyes, and 1-µm spherical AFM tips to probe the region immediately below the tissue surface. To localize flow resistance, perfusion and imaging methods were used to characterize the pressure drop in the immediate vicinity of the inner wall using giant vacuoles that form in Schlemm’s canal cells as micropressure sensors. Tissue stiffness increased with increasing AFM indentation depth. Tissues from glaucomatous eyes were stiffer compared with normal eyes, with greatly increased stiffness residing within ∼1 µm of the inner-wall surface. Giant vacuole size and density were similar in normal and glaucomatous eyes despite lower flow rate through the latter due to their higher flow resistance. This implied that the elevated flow resistance found in the glaucomatous eyes was localized to the same region as the increased tissue stiffness. Our findings implicate pathological changes to biophysical characteristics of Schlemm’s canal endothelia and/or their immediate underlying extracellular matrix as cause for ocular hypertension in glaucoma.

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