# eNOS-Dependent Mechanoregulation of Intraocular Pressure

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $439,697

## Abstract

Ocular hypertension in glaucoma arises from increased drainage resistance for aqueous humor in the
conventional outflow pathway, which includes the trabecular meshwork (TM) and Schlemm’s canal (SC).
Unfortunately, the cellular mechanisms responsible for resistance generation are largely unknown. Our previous
funding cycles have demonstrated that nitric oxide (NO) is a key regulator of outflow resistance and intraocular
pressure (IOP). Moreover, we have shown that shear stress stimulates NO production by SC endothelial cells,
like vascular endothelia. Further, the magnitude of shear stress acting on SC cells depends on IOP, due to
pressure-induced narrowing of the SC lumen. As NO is known to decrease outflow resistance, shear-induced
NO production may act as a “fast” homeostatic signal to oppose the source of IOP elevation and help to maintain
IOP in a narrow range. This “fast” homeostasis is sensed by SC shear stress and operates over time scales of
seconds to minutes, and contrasts with the “slow” IOP homeostasis that is sensed by TM stretch that stimulates
extracellular matrix (ECM) remodeling over several days. These “fast” and “slow” mechanisms are
complementary because they allow the outflow pathway to sense and respond to perturbations in outflow
function over a range of temporal scales, from acute outflow obstruction to chronic remodeling of ECM. Our
recent data provide further insight into the homeostatic role of NO and how NO maintains the health and function
of the conventional outflow pathway. For example, our data show that NO production by SC cells is amplified by
pulsatile shear stress, which arises due to the ocular pulse and results in an immediate pulsation-induced
decrease in outflow resistance. We also show that NO contributes to the clearance of particulate matter, such
as pigment and cell debris, that would naturally accumulate in the juxtacanalicular TM. Thirdly, our modelling
studies suggest that elevated TM stiffness (as occurs in primary open angle glaucoma; POAG) eliminates the
“fast” IOP homeostasis by suppressing pulsation-induced shear stress in SC. Consequently, this desensitization
allows debris to accumulate unchecked in the TM, leading to eventual outflow dysfunction and IOP elevation.
Taken together, our central hypothesis is that NO has two critical roles in maintaining IOP homeostasis over
short time scales: (i) as a key signaling molecule in a mechanosensitive feedback loop potentiated by pulsatile
shear stress in the SC lumen, and (ii) as a modulator of inner wall permeability and TM contractility to flush cell
debris/pigment from the juxtacanalicular TM. We test our hypothesis with three Specific Aims (SAs).
SA1: To determine how the ocular pulse modulates outflow facility through NO signaling.
SA2: To determine how NO contributes to IOP homeostasis in response to particulate load in the TM.
SA3: To determine how NO regulates inner wall permeability, enabling particulate clearance from the TM.
Impact: Outcom...

## Key facts

- **NIH application ID:** 10886574
- **Project number:** 5R01EY022359-13
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** DARRYL R OVERBY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $439,697
- **Award type:** 5
- **Project period:** 2012-04-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886574

## Citation

> US National Institutes of Health, RePORTER application 10886574, eNOS-Dependent Mechanoregulation of Intraocular Pressure (5R01EY022359-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10886574. Licensed CC0.

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