Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction

Abstract

Ocular hypertension in glaucoma develops due to age-related cellular dysfunction in the conventional outflow tract, resulting in increased resistance to aqueous humor outflow. Two cell types, trabecular meshwork (TM) and Schlemm's canal (SC) endothelia, interact in the juxtacanalicular tissue (JCT) region of the conventional outflow tract to regulate outflow resistance. Unlike endothelial cells lining the systemic vasculature, endothelial cells lining the inner wall of SC support a transcellular pressure gradient in the basal to apical direction, thus acting to push the cells off their basal lamina. The resulting biomechanical strain in SC cells is quite large and is likely to be an important determinant of endothelial barrier function, outflow resistance and intraocular pressure. This review summarizes recent work demonstrating how biomechanical properties of SC cells impact glaucoma. SC cells are highly contractile, and such contraction greatly increases cell stiffness. Elevated cell stiffness in glaucoma may reduce the strain experienced by SC cells, decrease the propensity of SC cells to form pores, and thus impair the egress of aqueous humor from the eye. Furthermore, SC cells are sensitive to the stiffness of their local mechanical microenvironment, increasing their own cell stiffness and modulating gene expression in response. Significantly, glaucomatous SC cells appear to be hyper-responsive to substrate stiffness. Thus, evidence suggests that targeting the material properties of SC cells will have therapeutic benefits for lowering intraocular pressure in glaucoma.

Influence of the Water-Drinking Test on Intraocular Pressure, Schlemm's Canal, and Autonomic Nervous System Activity

“…16 As pathologic changes in SC can result in significant resistance to aqueous humor outflow, [17][18][19][20][21] SC has attracted considerable interest as a target for glaucoma therapy in recent years (e.g., canaloplasty, viscocanalostomy, and SC scaffolding). 16 Given the superb images obtained with the EDI-OCT's anterior segment module, we were able to describe the details of SC in vivo.…”

A biomimetic Schlemm's canal inner wall: A model to study outflow physiology, glaucoma pathology and high-throughput drug screening

“…In glaucoma, drainage of aqueous humor into the Schlemm's canal is hindered, leading to an increase in intraocular pressure (IOP) and subsequent damage to the optic nerve, resulting in progressive loss of sight. Several studies have documented pathological changes to the SC inner wall in glaucoma 1-4 , implicating it as a significant contributor to increased outflow resistance 5 and thus, to elevated IOP. As a result, characterizing the physiology and pathology of the SC inner wall has attracted significant attention and consideration as a possible target for conventional outflow tract-targeted therapies, leading to glaucoma treatment 6 .…”

“…As a result, characterizing the physiology and pathology of the SC inner wall has attracted significant attention and consideration as a possible target for conventional outflow tract-targeted therapies, leading to glaucoma treatment 6 . The SC inner wall is a unique endothelial tissue that is specialized to handle basal to apical transendothelial pressure-dependent flow 5 . Together with the JCT of the human trabecular meshwork (HTM), the human SC (HSC) regulates and maintains proper IOP homeostasis.…”

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

“…Despite the fact that IOP is generated by conventional outflow resistance, IOP-lowering drugs that target this pathway are only beginning to be realized3. Furthermore, the molecular mechanisms that control pressure-dependent outflow are not well understood, but mechanotransduction in TM and SC cells appears critical4567.…”