Aqueous outflow regulation – 21st century concepts

Abstract

We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm’s canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.

Valve-Like Outflow System Behavior With Motion Slowing in Glaucoma Eyes: Findings Using a Minimally Invasive Glaucoma Surgery–MIGS-Like Platform and Optical Coherence Tomography Imaging

“…Loss of TM motion in glaucoma is consistent with this report's key concepts: the aqueous outflow system controls IOP by acting as a regulatory pump-conduit system (6,7,32,33). IOP-dependent tissue motion provides sensory input, while alterations in pathway dimensions serve the motor function of regulating flow.…”

Valve-Like Outflow System Behavior With Motion Slowing in Glaucoma Eyes: Findings Using a Minimally Invasive Glaucoma Surgery–MIGS-Like Platform and Optical Coherence Tomography Imaging

“…Loss of TM motion in glaucoma is consistent with this report's key concepts: the aqueous outflow system controls IOP by acting as a regulatory pump-conduit system (6,7,32,33). IOP-dependent tissue motion provides sensory input, while alterations in pathway dimensions serve the motor function of regulating flow.…”

Effects of Schlemm’s Canal Suture Implantation Surgery and Pilocarpine Eye Drops on Trabecular Meshwork Pulsatile Motion

“…Post-operative volume variability increased due to the SC serving as a reservoir for aqueous humor. The physiological outflow pattern of aqueous humor has been confirmed as a pump regulation theory, the mechanism of which involves changes in the IOP, causing compliant deformation of the TM, which leads to a cascading movement of valve-like tissues within the SC [19]. Previous studies in live subjects [36] have observed a pulsatile outflow of aqueous humor [37].…”

Age-Related Dysregulation of α5β1 and αvβ3 Integrin Activity Alters Contractile Properties of Trabecular Meshwork Cells

“…αSMA plays a pivotal role in cell contraction and is considered one of the markers of EndoMT associated with fibrosis and the pathogenesis of POAG. 2 , 3 Using immunofluorescence microscopy, we saw an increase in the localization of αSMA within stress fibers in α5-negative N77 TM cells compared to the α5-positive N27-2 TM cells ( Figs. 4 E, 4 F) in which αSMA was diffusely localized throughout the cells.…”

Valve-Like Outflow System Behavior With Motion Slowing in Glaucoma Eyes: Findings Using a Minimally Invasive Glaucoma Surgery–MIGS-Like Platform and Optical Coherence Tomography Imaging

“…Loss of TM motion in glaucoma is consistent with this report's key concepts: the aqueous outflow system controls IOP by acting as a regulatory pump-conduit system (6,7,32,33). IOP-dependent tissue motion provides sensory input, while alterations in pathway dimensions serve the motor function of regulating flow.…”

Effects of Schlemm’s Canal Suture Implantation Surgery and Pilocarpine Eye Drops on Trabecular Meshwork Pulsatile Motion

“…Post-operative volume variability increased due to the SC serving as a reservoir for aqueous humor. The physiological outflow pattern of aqueous humor has been confirmed as a pump regulation theory, the mechanism of which involves changes in the IOP, causing compliant deformation of the TM, which leads to a cascading movement of valve-like tissues within the SC [19]. Previous studies in live subjects [36] have observed a pulsatile outflow of aqueous humor [37].…”

Age-Related Dysregulation of α5β1 and αvβ3 Integrin Activity Alters Contractile Properties of Trabecular Meshwork Cells

“…αSMA plays a pivotal role in cell contraction and is considered one of the markers of EndoMT associated with fibrosis and the pathogenesis of POAG. 2 , 3 Using immunofluorescence microscopy, we saw an increase in the localization of αSMA within stress fibers in α5-negative N77 TM cells compared to the α5-positive N27-2 TM cells ( Figs. 4 E, 4 F) in which αSMA was diffusely localized throughout the cells.…”

Valve-Like Outflow System Behavior With Motion Slowing in Glaucoma Eyes: Findings Using a Minimally Invasive Glaucoma Surgery–MIGS-Like Platform and Optical Coherence Tomography Imaging

“…Loss of TM motion in glaucoma is consistent with this report's key concepts: the aqueous outflow system controls IOP by acting as a regulatory pump-conduit system (6,7,32,33). IOP-dependent tissue motion provides sensory input, while alterations in pathway dimensions serve the motor function of regulating flow.…”

Effects of Schlemm’s Canal Suture Implantation Surgery and Pilocarpine Eye Drops on Trabecular Meshwork Pulsatile Motion

“…Post-operative volume variability increased due to the SC serving as a reservoir for aqueous humor. The physiological outflow pattern of aqueous humor has been confirmed as a pump regulation theory, the mechanism of which involves changes in the IOP, causing compliant deformation of the TM, which leads to a cascading movement of valve-like tissues within the SC [19]. Previous studies in live subjects [36] have observed a pulsatile outflow of aqueous humor [37].…”

Age-Related Dysregulation of α5β1 and αvβ3 Integrin Activity Alters Contractile Properties of Trabecular Meshwork Cells

“…αSMA plays a pivotal role in cell contraction and is considered one of the markers of EndoMT associated with fibrosis and the pathogenesis of POAG. 2 , 3 Using immunofluorescence microscopy, we saw an increase in the localization of αSMA within stress fibers in α5-negative N77 TM cells compared to the α5-positive N27-2 TM cells ( Figs. 4 E, 4 F) in which αSMA was diffusely localized throughout the cells.…”