Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction
Introduction
The elevated intraocular pressure (IOP) that is associated with primary open-angle glaucoma (POAG) is caused by an increased resistance to the outflow of aqueous humor from the eye through the conventional2 outflow pathway (Grant, 1951). In spite of over 140 years of investigation (Leber, 1873), the precise cause of this increased outflow resistance remains elusive. Interestingly, most treatments for glaucoma focus on diminishing the rate of aqueous humor formation or altering the outflow path. These treatments lower IOP and thereby slow the progression of ganglion cell damage and associated vision loss, but in most cases do not stop it (Hattenhauer et al., 2000, Hattenhauer et al., 1998, Leske et al., 2003, Nouri-Mahdavi et al., 2004). Remarkably, there is currently no drug treatment in clinical use that directly targets the increased flow resistance that is a central characteristic of ocular hypertension in glaucoma, mainly because the mechanism(s) of increased flow resistance remain obscure.
Logically, the primary pathology underlying increased outflow resistance might be cellular, extracellular, or some combination of the two. Cellular contributions might include altered hydraulic conductivity of the endothelial lining of Schlemm's canal (SC), and extracellular contributions might include increased extracellular matrix in the juxtacanalicular tissue (JCT) or altered basement membrane beneath SC cells; however, comparisons of the outflow pathways of glaucomatous and age-matched normal eyes have found only subtle structural differences. Specifically, in glaucoma, there is an accelerated loss of trabecular meshwork (TM) cells that is limited to the inner region of the conventional outflow pathway (Alvarado et al., 1981, Alvarado et al., 1984) and cytoskeletal changes in the actin architecture of JCT-TM3 and SC cells (Read et al., 2007). Additionally, there is an accumulation of a “sheath derived plaque material” in the JCT of glaucomatous eyes (Alvarado et al., 1986, Lutjen-Drecoll et al., 1981), but this accumulation has been shown to have negligible hydrodynamic consequence (Alvarado et al., 1986) (Murphy et al., 1992). There is little other morphological evidence of increased extracellular matrix or altered basement membrane composition in glaucomatous eyes compared to age-matched controls.
At the level of SC, however, several changes in glaucomatous eyes have been observed with the potential to be a significant contributor to the increased outflow resistance. The dimensions of the lumen of SC are smaller in glaucomatous eyes and these changes correlate with outflow resistance (Allingham et al., 1996). Herniations of the inner wall and JCT tissue into collector channels are more frequently observed in glaucomatous eyes than age-matched non-glaucomatous eyes (Gong et al., 2007, Hann et al., 2014). There is also a reduced pore density in the inner wall endothelium of SC comparing normal to glaucomatous eyes (Allingham et al., 1992, Johnson et al., 2002) that is potentially quite important. Collectively, these data point to dysfunction at the level of the inner wall of SC in glaucoma.
In this article, we review recent evidence that increased stiffness of SC endothelial cells is responsible for the elevated outflow resistance and IOP characteristic of glaucoma; we also present data showing that drugs that change cell stiffness also alter outflow resistance. By understanding the coupling between biomechanics and flow through the inner wall endothelium, we outline opportunities to exploit cell biomechanics as a targeted approach to reduce IOP at the site of outflow resistance regulation.
Section snippets
The inner wall endothelium of Schlemm's canal experiences a unique biomechanical environment
The typical pressure loading on vascular endothelia generates a pressure gradient in the apical to basal direction. The basement membrane and other tissues underlying vascular endothelia amply support the transcellular pressure drop generated by this gradient, and thus the vascular endothelial cells themselves do not have to support the associated radial and circumferential stresses. This is not the case for the endothelium of SC, where the SC cells themselves must support a “backwards” basal
Conclusions
SC cells are surprisingly contractile, capable of changing their contractile state to employ forces that are comparable to those exerted by smooth muscle cells in the lung (Zhou et al., 2012). While the source of resistance to the flow of aqueous humor through its primary outflow pathway from the eye is still a topic of active research (Keller and Acott, 2013, Overby et al., 2009, Swaminathan et al., 2013), a number of laboratories have now converged on the hypothesis that the contractile state
Future directions
To develop new therapeutic strategies that specifically target SC cells, progress in several areas is needed. First, better mechanistic understanding of the pore forming machinery in SC cells will provide novel targets for intervention. For example, it may be helpful to apply knowledge from mechanistic studies of fenestrae formation or transcellular diapedesis to intracellular pore formation in SC cells (Michel and Neal, 1999). Second, a better understanding of the molecular changes in
Funding support
NIH grants (EY019696, EY022359, HL120839 and HL107561), BrightFocus Foundation, Research to Prevent Blindness Foundation, Georgia Research Alliance and Royal Society Wolfson Research Merit Award.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Stamer: 20%; Braakman: 10%, Zhou: 10%; Ethier: 15%; Fredberg: 10% Overby: 15%; Johnson: 20%.