Altered mechanobiology of Schlemm’s canal endothelial cells in glaucoma

Abstract

Increased flow resistance is responsible for the elevated intraocular pressure characteristic of glaucoma, but the cause of this resistance increase is not known. We tested the hypothesis that altered biomechanical behavior of Schlemm's canal (SC) cells contributes to this dysfunction. We used atomic force microscopy, optical magnetic twisting cytometry, and a unique cell perfusion apparatus to examine cultured endothelial cells isolated from the inner wall of SC of healthy and glaucomatous human eyes. Here we establish the existence of a reduced tendency for pore formation in the glaucomatous SC cell-likely accounting for increased outflow resistance-that positively correlates with elevated subcortical cell stiffness, along with an enhanced sensitivity to the mechanical microenvironment including altered expression of several key genes, particularly connective tissue growth factor. Rather than being seen as a simple mechanical barrier to filtration, the endothelium of SC is seen instead as a dynamic material whose response to mechanical strain leads to pore formation and thereby modulates the resistance to aqueous humor outflow. In the glaucomatous eye, this process becomes impaired. Together, these observations support the idea of SC cell stiffness-and its biomechanical effects on pore formation-as a therapeutic target in glaucoma.cell mechanics | primary open-angle glaucoma | modulus | cytoskeleton

Trabecular Meshwork Response to Pressure Elevation in the Living Human Eye

“…The locations of greatest outflow resistance are the juxtacanicular tissue and the inner wall of Schlemm canal (SC), the interface between SC and the trabecular meshwork (TM) [9][10][11] . While TM stiffness may contribute to the prevention of SC collapse in the face of IOP elevation, Overby et al 12 recently demonstrated that gene expression in glaucoma is altered, resulting in increased SC endothelial stiffening, impeding formation of pores, leading to IOP elevation in glaucomatous eyes 13 . TM morphology and stiffness correlate with outflow facility 14,15 , emphasizing the need to measure its biomechanical characteristics.…”

Elevated Intraocular Pressure induces Ultrastructural Changes in the Trabecular Meshwork

“…These studies were done in isolated cultured endothelial cells of the inner wall of Schlemm's canal. These authors further proposed that inner wall of endothelium plays a fundamental role in generating increased resistance and pore formation in the inner wall of endothelium of Schlemm's canal which could modulate aqueous humour flow resistance through a hydrodynamic interaction with flow of aqueous humour passing through the trabecular meshwork [11].…”

“…The structures responsible for such an increase include JCT and SC [30][31][32][33]. In a recent paper Overby et al [11] showed that endothelium of the Schlemm's canal that lead to pore formation modulates the outflow resistance. In glaucomatous eyes there were reduced numbers of pores that led to the increase in the outflow resistance.…”

“…Overby et al [11] found that endothelial cells showed changes in the gene expression correlated with increased outflow resistance of the aqueous humor. A positive correlation was also found with cell stiffness together with changes in the connective tissue growth factor.…”

“…Other researchers found no difference in the number of giant vacuoles in normal and glaucomatous eye. However, in a recent study Overby et al [11] showed that increased cytoskeletal stiffness of the Schlemm's canal endothelial cells lead to reduced pore formation by these cells.…”