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

ABSTRACT

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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    • "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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