January 2020

OPHTHALMOLOGY

SITE OF FLOW RESISTANCE IN GLAUCOMA IDENTIFIED

Featuring: Mark Johnson, PhD

Northwestern Medicine scientists may have solved a 150-year old mystery of glaucoma: what causes elevated pressure in the eye?

According to findings published in Proceedings of the National Academy of Sciences, the answer lies within in the wall of in a small vessel in the eye called the Schlemm’s canal endothelium, the last stop for ocular fluid as it travels out of the eye to the bloodstream. In glaucoma, this layer of cells becomes abnormally stiff, preventing fluid from flowing out of the eye and leading to increased intra-ocular pressure.

“We’ve localized exactly where the change is occurring in glaucoma,” said Mark Johnson, PhD, professor of Ophthalmology and of Biomedical Engineering at the McCormick School of Engineering. “This could be very significant in terms of finding a cure for this disease.”

The eye uses a transparent fluid called aqueous humor for nutrition; the fluid is secreted from behind the iris, circulates past the lens and cornea before exiting the eye through a complicated pathway in the sclera. There, the aqueous humor moves though a fine tissue called the trabecular meshwork and must cross Schlemm’s canal endothelium — the lining of the vessel — before reaching Schlemm’s canal proper, which dispenses aqueous humor into the bloodstream.

In glaucoma, however, this outflow is blocked, causing a buildup of aqueous humor and raising pressure throughout the eye. This has been known this for nearly 150 years, but up until now the precise location where this blockage occurs has been scientists.

“People have been looking at this outflow pathway for a long time and nobody’s been able to see exactly what’s different in glaucoma,” Johnson said.

Building on recent work that identified increased tissue stiffness in these areas, Johnson and his colleagues used atomic force microscopy to search for micro-level changes in tissue stiffness. They found that the trabecular meshwork hadn’t changed — instead, it was the lining of Schlemm’s canal that exhibited increased stiffness. In particular the substrate of the endothelial cells lining Schlemm’s canal was stiffer by an order of magnitude, according to the investigators.

To relate this increased stiffness to outflow resistance that would lead to elevated pressure in the eye, Johnson and his collaborators  observed small cellular bubbles called giant vacuoles, located in the Schlemm’s canal endothelium. Using these bubbles as “micro-pressure sensors,” they found that the increased ocular pressure in glaucomatous eyes was generated at this same location.  “In the exact region where you have increased stiffness, you are also seeing increased flow resistance,” Johnson said. “Right there, that’s what’s causing the increased pressure in glaucoma.”

Now that the location of increased stiffness and flow resistance in glaucoma has been identified, scientists can work to devise a cure for this chronic condition. A recently developed treatment for glaucoma uses rho-kinase inhibitors to soften the Schlemm’s canal cells and thereby lower outflow resistance and intraocular pressure. However, this treatment softens other cell types in the eye, causing side effects.

Instead, Johnson believes that specifically targeting the Schlemm’s canal endothelium cells could result in a longer-lasting and more specific treatment. “If we can figure out some way to genetically target the Schlemm’s canal cells, we can make them softer,” Johnson said. “They’ll let more fluid flow through and that might be a more permanent solution to the problem.”
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This study was supported by National Institutes of Health grants EY019696 and EY022634.

This article was originally published in the Feinberg School of Medicine News Center on January 13, 2020. 
Mark Johnson, PhD, professor of McCormick School of Engineering and professor in the Division of Ophthalmology at Northwestern Medicine. 

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