June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Mechanoregulation of IOP by Nitric Oxide Predicts the “Washout” Phenomenon
Author Affiliations & Notes
  • Darryl R Overby
    Bioengineering, Imperial College London, London, London, United Kingdom
  • Ruth A Kelly
    Duke University Department of Ophthalmology, Durham, North Carolina, United States
  • Changxu Miao
    Bioengineering, Imperial College London, London, London, United Kingdom
  • Ester Reina-Torres
    Bioengineering, Imperial College London, London, London, United Kingdom
  • W Daniel Stamer
    Duke University Department of Ophthalmology, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Darryl Overby None; Ruth Kelly None; Changxu Miao None; Ester Reina-Torres None; W Daniel Stamer None
  • Footnotes
    Support  NIH grant EY022359, EY033142 and BrightFocus grant G2020-003
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3460. doi:
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      Darryl R Overby, Ruth A Kelly, Changxu Miao, Ester Reina-Torres, W Daniel Stamer; Mechanoregulation of IOP by Nitric Oxide Predicts the “Washout” Phenomenon. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3460.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Intraocular pressure (IOP) elevation causes narrowing of the Schlemm’s canal (SC) lumen, which increases the hydrodynamic shear stress acting on SC cells. Elevated shear stress stimulates nitric oxide (NO) production by SC cells, which acts to: (i) reduce outflow resistance, R, to offset IOP elevation; and (ii) relax trabecular meshwork (TM) cells to reduce TM stiffness, E. Thus, NO provides an IOP-sensitive feedback signal for IOP homeostasis (Reina-Torres et al.PRER, 2021; Figure 1). We hypothesise that this feedback mechanism should exhibit an instability during constant pressure perfusion, because NO can no longer affect IOP, but can increase the flow rate and shear stress in SC to drive further NO production.

Methods : A simple mathematical model was formulated and analysed for stability. The model is based on Goldmann’s equation, accounting for proximal (R) and distal resistance, and includes relationships for shear stress in SC, NO production rate in terms of shear stress, and the height of SC in terms of E and the pressure drop across the TM. Additional relationships account for the sensitivity of R and E upon NO, represented by ρ and ξ respectively.

Results : During constant flow perfusion, which mimics the in vivo state of constant aqueous humour production by the ciliary body, the outflow system is largely stable, returning to its initial value of IOP following a perturbation. In contrast, during constant pressure perfusion, which mimics most experimental conditions to measure R, the system is largely unstable and exhibits a time-dependent decrease in R. Impressively, over the physiological range of ρ and ξ, the domain of instability was 70-fold larger for constant pressure relative to constant flow (Figure 2).

Conclusions : Shear-mediated IOP homeostasis is largely stable under conditions of constant inflow. However, during experimental perfusion to measure outflow facility at constant pressure, the feedback becomes unstable, predicting a time-dependent facility increase, consistent with the “washout” phenomenon. A better understanding of IOP homeostasis and NO signalling in SC and TM may explain the mechanism of outflow dysfunction in glaucoma.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Shear-mediated IOP homeostasis involving NO that acts to reduce outflow resistance R and TM stiffness E.

Shear-mediated IOP homeostasis involving NO that acts to reduce outflow resistance R and TM stiffness E.

 

Constant flow perfusion exhibits greater stability (yellow) and less instability (blue) relative to constant pressure perfusion.

Constant flow perfusion exhibits greater stability (yellow) and less instability (blue) relative to constant pressure perfusion.

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