The mechanobiology of the inner wall endothelium of Schlemm's Canal

Glaucoma is the leading cause of irreversible blindness worldwide. The main risk factor for glaucoma is elevated intraocular pressure caused by increased resistance to aqueous humour (AH) flow in the region near the inner wall endothelium of SC. In the healthy eye, AH flow across the SC endothelium generates a basal-to-apical transendothelial pressure drop, which tends to push the cells off their basement membrane and inflates dome-shaped structures known as giant vacuoles (GVs). GV formation leads to substantial cell thinning associated with formation of transendothelial pores that provide a flow pathway across the SC endothelium. Our overarching hypothesis is that the coupled interaction between transendothelial basal-to-apical pressure drop, and GV and pore formation, is centrally involved the regulation of flow resistance and IOP. We examined this hypothesis across four studies carried out using an in vitro model of SC endothelium that mimicked the in vivo basal-to-apical transendothelial pressure drop. A first study demonstrated that GV-like structures (GVLs) form in perfused SC endothelial (SCE) cells and that they can retract against a load likely through an actomyosin-dependent process. A second study demonstrated that a proportion of GVLs are surrounded by an F-actin band that presumably contracts during GVL retraction. Together these findings suggest that SCE cells can modulate GV dynamics, which may be important for outflow resistance regulation. The third study showed that the hydraulic resistivity of SCE cell layers exhibits both pressure and time-dependent characteristics that likely reflect changes in the cell layer morphology. The study also highlighted that the existence of non-physiological intercellular gaps limits the interpretation of resistivity measurements. The final study established that culturing SCE cells under a long-term transendothelial pressure drop may overcome this limitation as it leads SCE cell layers to better reproduce key cytoskeletal, cellular and multicellular morphological characteristics of the SC endothelial barrier.Open Acces