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Editors Selection IGR 13-2

Basic Research: NO production by Schlemm's canal cells

Comment by Ross Ethier & Daniel Stamer & Darryl Overby on:

26980 Endogenous regulation of human Schlemm's canal cell volume by nitric oxide signaling., Ellis DZ; Sharif NA; Dismuke WM, Investigative Ophthalmology and Visual Science, 2010; 51: 5817-5824

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Ellis et al. (1537) have shown that Schlemm's canal (SC) endothelial cells respond to nitric oxide (NO) by changing their volume, with NO-donors reducing the volume of cultured SC cells in a dose-dependent manner. Conversly, inhibition of endogenous NO synthase was shown to have the reverse effect, suggesting basal levels of NO production by SC cells. This work is important because other studies have shown that NO increases outflow facility, that NO donors augment the ocular hypotensive effects of prostaglandin analogues, and because mutations in the NOS3 gene, coding for the enzyme endothelial NO synthase, are associated with ocular hypertension and glaucoma. Since aqueous humour flows through micron-sized pores and tortous pathways to cross SC endothelium as it drains from the eye, it is easy to imagine how SC cell volume changes could affect facility by either narrowing or widening the dimensions of these already minute pathways.

SC cell volume changes could affect facility by either narrowing or widening the dimensions of already minute pathways

It is well-known that NO generation is mechanosensitive in vascular endothelia, being highly upregulated in response to shear stress. If similar mechanosensory mechanisms exist in the outflow system, then NO would be a candidate autocrine or paracrine signal in an IOP-controlling feedback loop.

The authors used four human SC cell lines, increasing confidence in the robustness of their findings, and their mechanistic approach and use of inhibitors allowed them to identify signaling proteins involved in the NO response. Specifically, they show that these effects of NO are mediated through cGMP, PKG and the high conductance calcium-activated potassium channel, BK_Ca. It will be important to confirm these results, carried out on isolated SC cells, in the more relevant situation of confluent monolayers of SC cells, especially since NO has known effects on cell-cell attachments, and signaling pathways between junction assembly/disassembly and cell volume likely interact to maintain homeostasis. This work motivates study of the direct interaction between SC volume and outflow facilty in whole eye preparations.

Overby-Ethier-Stamer

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