Hydrodynamics of aqueous humor outflow

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness resulting from elevated intraocular pressure caused by a pathologic increase in the resistance to aqueous humor outflow from the eye. Currently, the physiological and ultrastructural bases for the generation of aqueous humor outflow resistance remain unclear in both the normal and glaucomatous eye, although experimental evidence suggests that the extracellular matrix within the juxtacanalicular connective tissue (JCT) is the principle resistive element. Johnson, Shapiro et al. (1992) have postulated that the resistance of the JCT is further increased by a hydrodynamic "funneling" interaction whereby the available area for aqueous flow through the JCT is reduced by the constraint that aqueous must cross the inner wall endothelium of Schlemm's canal through discrete pores. In this study, we focus on uncovering the role of the JCT in the generation of aqueous humor outflow resistance in the non-glaucomatous eye. Quick-freeze/deep-etch (QF/DE) electron microscopy was used to visualize the extracellular matrix within the JCT. A novel stereologic theory was developed to relate the two-dimensional void area and perimeter observed on a micrograph to the three-dimensional tissue porosity and specific surface, allowing the hydraulic resistance of an extracellular matrix to be estimated from a QF/DE micrograph. Extensive numerical studies were conducted to validate the predictions of the stereologic theory. To investigate the funneling effect,

(cont.) morphologic changes that would disrupt funneling were proposed and investigated to determine their role in the "washout" phenomenon (the progressive decrease in aqueous outflow resistance measured during experimental perfusion of non-human eyes). QF/DE revealed the presence of empty space devoid of extracellular matrix within the JCT. Washout was found to act through a reversible separation of the JCT from the basal lamina of the inner wall endothelium that was proposed to eliminate funneling. These results challenge the belief that aqueous outflow resistance is generated by extracellular matrix within the JCT. This study also suggests that the molecular components responsible for tethering the inner wall to the JCT are important regulators of aqueous humor outflow resistance in the normal eye and thereby represent potential targets for treatment of POAG.