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Editors Selection IGR 18-2

Basic Science: Schlemms endothelial cells

Comment by Darryl Overby on:

60132 Finite element analysis of the pressure-induced deformation of Schlemm's canal endothelial cells, Vargas-Pinto R; Lai J; Gong H et al., Biomechanics and modeling in mechanobiology, 2015; 14: 851-863

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The endothelium of Schlemm's canal (SC) serves a dual role. On one hand, SC endothelium must be conductive enough to allow aqueous humor to cross the endothelium, enter SC and drain from the eye. On the other hand, SC endothelium must be resistive enough to prevent blood or serum proteins from entering the anterior chamber from the episcleral veins, thereby maintaining the blood-aqueous barrier (BAB). To satisfy these divergent roles, SC endothelium must function as a one-way valve that opens in the direction of outflow, but closes to oppose retrograde flow. This one-way valve function appears to be regulated by the biomechanics of SC cells. Prior work from this same group has identified that the biomechanical stiffness of SC cells increases in glaucoma, which could potentially disrupt SC valve function, impede outflow and elevate IOP.

To understand how SC cell biomechanics influences outflow physiology, Rocio Vargas-Pinto and colleagues use computer modeling to demonstrate how SC cells deform in response to a transendothelial pressure drop as occurs in vivo. This is relevant because SC cell deformation is thought to trigger the formation of micron-sized transendothelial openings (pores), the presumed site where aqueous crosses SC endothelium when draining from the eye. This mechanism allows SC cells to localize pore formation to sites of sufficient filtration demand, while maintaining relatively low porosity elsewhere so as to preserve the BAB. Vargas-Pinto et al. convincingly demonstrate that the cortical cytoskeleton bears most of the biomechanical load acting on SC cells such that increasing cortical stiffness or thickness allows SC cells to support greater loads. When prescribing values of cell stiffness measured in vitro, however, SC cells were able to support only a fraction of the pressure drop across the outflow pathway. This important result suggests that the majority of the pressure drop may not lie across SC cells themselves, but elsewhere in the outflow pathway, presumably across the extracellular matrix underlying SC endothelium. Alternatively, SC cells in vivo may be considerably well adapted to withstand even greater loads than predicted by computer simulations, presumably on account of increased cell or cortical stiffness or specialized cell-cell or cell-matrix attachments.

This elegant bioengineering study brings to light several questions that are fundamental to the pathogenesis of ocular hypertension in glaucoma. Namely, what is the stiffness of SC cells in vivo? What is the biomechanical mechanism of pore formation? What is responsible for elevated SC cell stiffness in glaucoma? Ultimately, this work points to a new therapy to improve aqueous humor outflow and lower IOP by targeting SC cell stiffness, but the success of such a therapy depends on understanding the intricate coupling between outflow and SC cell biomechanics. The excellent work by Vargas-Pinto and colleagues describes this coupling and brings us closer to realizing the dream of a conventional outflow drug that targets the root pathology of ocular hypertension in open-angle glaucoma.

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