Interactions between endothelia of the trabecular meshwork and of Schlemm's canal: a new insight into the regulation of aqueous outflow in the eye.
OBJECTIVE
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.
Alvarado
Jorge A
JA
Department of Ophthalmology, University of California San Francisco, USA.
Yeh
Ru-Fang
RF
Franse-Carman
Linda
L
Marcellino
George
G
Brownstein
Michael J
MJ
D001082:Aqueous Humor / Q000502:physiology* / Q000528:radiation effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007834:Lasers; D008024:Ligands; D012333:RNA, Messenger / Q000378:metabolism; D012590:Sclera / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects
D017077:Culture Media, Conditioned; D016207:Cytokines; D008024:Ligands; D012333:RNA, Messenger