Interactions between endothelia of the trabecular meshwork and of Schlemm's canal: A new insight into the regulation of aqueous outflow in the eye


Purpose: To test the hypothesis that trabecular meshwork endothelial cells (TMEs) regulate aqueous outflow by actively releasing ligands that upon binding to Schlemm's canal endothelial cells (SCEs) increase transendothelial flow, thereby facilitating the egress of aqueous. Methods: We tested our hypothesis by (1) activating the TMEs in vitro using a laser procedure known to increase aqueous outflow in vivo; (2) demonstrating that lasered TMEs become activated at the genome-wide level and synthesize ligands; (3) ascertaining that media conditioned by laser-activated TMEs and ligands therein increase transendothelial flow when added to SCEs; and (4) determining that ligands identified as synthesized by TMEs increase permeability when added to SCEs. Results: We find that adding either media conditioned by lasered TMEs or ligands synthesized by TMEs to naïve control SCEs increases permeability. Adding media boiled, diluted, or conditioned by nonlasered TMEs abrogates these permeability effects. Media conditioned by either lasered TMEs or SCEs (TME-cm/SCE-cm), when added to untreated controls of each cell type, induce congruous gene expression and flow effects: TME-cm induces far more differentially expressed genes (829 in control TMEs and 1,120 in control SCEs) than does the SCE-cm (12 in control TMEs and 328 in control SCEs), and TME-cm also increases flow much more (more than 11-fold in control TMEs and more than fourfold in control SCEs) than does the SCE-cm (fivefold in control TMEs and twofold in control SCEs). Conclusions: As postulated, the TMEs release factors that regulate SCE permeability. Derangement of this TME-driven process may play an important role in the pathogenesis of glaucoma. Ligands identified, which regulate permeability, have potential use for glaucoma therapy.

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Available from: Michael Brownstein, Jun 30, 2015
    • "The interactions between TMes and SCes occur in both directions and involve relationships within both barriers. These interactions allow these cells to release factors such as enzymes and cytokines, including IL1a, IL1b, and IL8, probably by inducing the dis-assembly of intercellular junctions (Alvarado and Shifera, 2010), and could affect the TMes lining the outermost aqueous channels, which must be crossed before AH can pass into the JCT (Alvarado et al., 2005b). Moreover, TNFa induces cell division and migration (Bradley et al., 2000) in those cells near Schwalbe's line, while inducing the release of MMPs (Kelley et al., 2007b). "
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    ABSTRACT: The trabecular meshwork plays an important role in high-tension glaucomas. Indeed, the TM is a true organ, through which the aqueous humor flows from the anterior chamber to Schlemm's canal. Until recently, the TM, which is constituted by endothelial-like cells, was described as a kind of passive filter. In reality, it is much more. The cells delineating the structures of the collagen framework of the TM are endowed with a cytoskeleton, and are thus able to change their shape. These cells also have the ability to secrete the extracellular matrix, which expresses proteins and cytokines, and are capable of phagocytosis and autophagy. The cytoskeleton is attached to the nuclear membrane and can, in millionths of a second, send signals to the nucleus in order to alter the expression of genes in an attempt to adapt to biomechanical insult. Oxidative stress, as happens in aging, has a deleterious effect on the TM, leading eventually to cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility and (ultimately) increased IOP. TM failure is the most relevant factor in the cascade of events triggering apoptosis in the inner retinal layers, including ganglion cells. This article is protected by copyright. All rights reserved
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    • "In microvascular and lymphatic endothelia with less well-developed intercellular junctions , leukocyte diapedesis occurs predominantly paracellularly (Carman et al., 2007). Similarly, the pore type in SC endothelium may depend on the quality of the local junctions or paracrine or autocrine signals from TM, JCT and/or SC cells potentially mediated by physical cues related to IOP or outflow (Alvarado et al., 2005). In conclusion, this study demonstrated a colocalization between paracellular B-pores and local tracer accumulation along the inner wall of SC in human eyes perfused with fluorescent tracer nanospheres . "
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    ABSTRACT: All aqueous humor draining through the conventional outflow pathway must cross the endothelium of Schlemm's canal (SC), likely by passing through micron-sized transendothelial pores. SC pores are non-uniformly distributed along the inner wall endothelium, but it is unclear how the distribution of pores relates to the non-uniform or segmental distribution of aqueous humor outflow through the trabecular meshwork. It is hypothesized that regions in the juxtacanalicular tissue (JCT) with higher local outflow should coincide with regions of greater inner wall pore density compared to JCT regions with lower outflow.
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    ABSTRACT: Aqueous humor is actively produced in the ciliary epithelium of the anterior chamber and has important functions for the eye. Under normal physiological conditions, the inflow and outflow of the aqueous humor are tightly regulated, but in the pathologic state this balance is lost. Aqueous outflow involves structures of the anterior chamber and experiences most resistance at the level of the trabecular meshwork (TM) that acts as a filter. The modulation of the TM structure regulates the filter and its mechanism remains poorly understood. Proteomic analyses have identified cochlin, a protein of poorly understood function, in the glaucomatous TM but not in healthy control TM from human cadaver eyes. The presence of cochlin has subsequently been confirmed by Western and immunohistochemical analyses. Functionally, cochlin undergoes multimerization induced by shear stress and other changes in the microenvironment. Cochlin along with mucopolysaccharide deposits has been found in the TM of glaucoma patients and in the inner ear of subjects affected by the hearing disorder DNFA9, a late-onset, progressive disease that also involves alterations in fluid shear regimes. In vitro, cochlin induces aggregation of primary TM cells suggesting a role in cell adhesion, possibly in mechanosensation, and in modulation of the TM filter.
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