Aqueous Humor Drainage

What are the two pathways of Aqueous Humor drainage?

Conventional route and Uveoscleral/unconventional route

What is the conventional route of aqueous humor drainage?

Through the trabecular meshwork, across inner wall of Schlemm’s canal into its lumen, through collector channels, deep sclera/intrascleral/episcleral plexus (aqueous veins), and the episcleral vein

What is the uveoscleral/unconventional route of aqueous humor drainage?

Across the iris root, uveal meshwork, and anterior face of the ciliary muscle, through the connective tissue between bundles, into the suprachoroidal space, and through the sclera

What route is more common for aqueous humor drainage?

Conventional route (~45-65% of AH leaves the eye through trabecular meshwork and Schlemm’s canal)

What is outflow pressure (driving the movement of aqueous through Schlemm’s canal) dependent on?

IOP

An increase in IOP causes a/n (increase/decrease) in drainage through trabecular meshwork.

Increase

What is the effect of IOP on the uveoscleral pathway?

Typically independent of IOP

What is the general shape of trabecular meshwork in cross section?

Triangular-like shape

Where does trabecular meshwork begin and end?

Begins at Schwalbe’s line (end of Descemet’s) and posterior end is bordered by the scleral spur and infiltrated by ciliary muscle tendons

Where is the Trabecular meshwork relative to Schlemm’s canal and what does it provide?

Underlies Schlemm’s canal and provides resistance to outflow (conventional)

What are the three interconnecting layers that comprise the Trabecular meshwork?

Uveal, Corneoscleral, Juxtacanalicular

Describe the general shape/appearance of uveal meshwork?

Small, roundish branching trabeculae (around 4um in diameter)

What do the spaces between uveal meshwork provide?

Little resistance to outflow and AH passes through easily

How many layers thick is Uveal meshwork?

1-3 layers thick and interconnected

What can processes of uveal meshwork occasionally extend to?

The iris

What is the origin point of corneoscleral meshwork?

Scleral spur

Describe the shape/appearance of Corneoscleral meshwork?

Broad sheet-like meshwork

How do the spaces in between corneoscleral meshwork compare to those of uveal meshwork?

Spaces are smaller than uveal meshwork (10-30um) and more elliptical

How many layers thick is Corneoscleral meshwork?

8-15 layers thick

How do adjacent sheets of corneoscleral meshwork relate to each other in space?

They are offset and not perfectly aligned (helps build resistance to outflow)

What do the torturous flow channels between the intertrabecular spaces of corneoscleral meshwork lead to?

Juxtacanalicular region (JCT)

What surrounds the trabecular lamellae (beams)?

Cells

What are trabecular lamellae made up of?

Glycoproteins, collagen fibrils, hyaluronic acid, and elastic fibers

What is found between cells and trabecular lamellae?

A continuous basememnt membrane

What are uveal/corneoscleral cells continuous with?

Schwalbe’s line cells and corneal endothelium

What trabecular meshwork nerves is there evidence for?

Sensory (mechanoreceptors) nerve endings and Sympathetic and parasympathetic innervation

What may trabecular meshwork nerves trigger cells to do?

Respond to stress or strain in connective tissue elements

How may cells respond to stress or strain in connective tissue elements due to TM nerve innervation?

Cellular contractility and ECM production

What is a main function of trabecular meshwork cells?

Phagocytic function that acts as a “self-cleaning” filter by breaking down cellular debris in AH

What does the phagocytic function of trabecular meshwork cells aid in?

Facilitates AH drainage

What is Juxtacanicular tissue?

Comprises of loose connective tissue with 2-5 layers of scattered TM cells that are embedded in a loosely arranged fibrillar extracellular matrix, hyaluronan, GAGs

What is Juxtacanalicular tissue adjacent to?

The endothelial cells lining inner Schlemm’s canal

Describe the basement membrane of Juxtacanalicular tissue?

Has a discontinuous basement membrane

What is the JCT a major site of?

Trabecular outflow resistance

Does the JCT change or remain static with age?

Changes with age

What gives trabecular meshwork an elastic quality?

An elastic plexus is found between the first corneascleral lamellae and the subepithelial cells of the JCT

What comprises the elastic plexus found between the first corneascleral lamellae and the subepithelial cells of the JCT?

Fibrillar and non-fibrillar collagen, elastin, GAG’s, proteoglycans, ECM remodeling proteins

What is continuous with the connecting fibrils of the elastic plexus?

Ciliary muscle tendons emanating from the scleral spur that enter the JCT

How are Schlemm’s canal endothelial cells connected to the ciliary muscle?

They are connected to ciliary muscle tendons in JCT via connecting fibrils of the elastic plexus

How are scleral spur cells connected to the trabecular meshwork?

Scleral spur cells are adhered to elastic fiber banded sheath material

What happens to trabecular meshwork when the ciliary muscle contracts?

Pulls on scleral spur and meshwork and increases aqueous outflow by creating more spaces in the meshwork and thinning the ECM

What occurs due to advanced age in relation to the trabecular meshwork?

1. A loss of TM cells

2. Increased ECM around elastic fibers

3. Increased flow resistance

What happens with a loss of TM cells with advanced age?

Can cause the inner uveal and corneascleral meshwork tissue to become “glued” together

Is there consistent IOP changes noted with age? Why or why not?

No because although there increased flow resistance, there is a decrease in aqueous production to compensate

How can trabecular meshwork be physiologically modified to change outflow rate?

1. Sustained elevated IOP can cause cells to allow more outflow

2. Due to mechanosensation of TM cells and their connections to the ECM

How are trabecular meshwork cells connected to the ECM?

Via integrins/focal adhesions which enables force to propogate from ECM to cells

What is the central role for focal adhesions in trabecular meshwork regulation?

Integrins bridge the extracellular basement membrane/ECM proteins (such as fibronectin), and the intracellular cytoskeleton comprised of acto-myosin filaments

What does a stretch in extracellular matrix do to TM cell contractility?

A stretch in ECM modifies actomyosin/cell contractility

What can actomyosin/cell contractility of TM cells modify?

1. Cell shape and mechanics

2. ECM production and remodeling

What is Piezo1 and what is its role?

An ion transport protein found within TM cells and allows ions through when the cell stretches (esp. due to elevated IOP)

What does activation of Piezo1 do and how does it affect TM cells?

Allows Ca2+ into TM cells and causes the release of PGE2, PGE2 causes the cell’s cytoskeletal network and therefore the cell itself to relax

What does relaxation of the cytoskeletal network in TM cells cause?

A drop in IOP due to less resistance to outflow

What does inhibiting Piezo1 do?

Decreases facility due to more resistance to outflow

What type of channel is Piezo 1?

A mechanosensing ion channel (acts a lot like TRP channels)

What does Piezo1 open in response to?

Membrane stretch

What does sitmulation of Piezo 1 cause? (recall)

Relaxation of trabecular meshwork cells via increase of calcium in cells

What molecule does relaxation of TM cells involve?

Cytoskeletal prostaglandins

What is Schlemm’s canal?

A circular structure that provides drainage for the AH and delivers it to venous return

How can the drainage into Schlemm’s canal be characterized?

Non-uniform drainage

Why is the drainage into Schlemm’s canal non-uniform?

Due to non-uniform ECM proteins in the JCT

What vasculature does Schlemm’s canal have?

Both blood vasculature and lymphatic vasculature

When AH drains from schlemm’s canal where does it go?

Into collector channels

How does the AH drain from Schlemm’s canal into collector channels?

Through 25-35 irregularly spaced openings into collector channels

Where do the collector channels receiving AH from Schlemm’s canal drain?

Some connect directly to the episcleral vein but most join the episcleral venous plexus

Is fluid movement and exit from Schlemm’s into collector channels uniform?

No, rates differ along circumference of Schlemm’s canal

What does the discovery of nerves being more commonly identified in regions that contained collector channels when compared to regions without collector channels in Schlemm’s canal, suggest?

Suggests an active neural regulation of AH outflow throughout the proximal and distal regions of the conventional outflow pathway (Research ongoing)

What is the general structure of Schlemm’s canal?

1. Comprised of an inner and outer wall (not bilayered)

2. Lined with endothelial cells connected by non-leaky tight-junctions

What does the inner wall of Schlemm’s canal face?

The juxtacanalicular tissue

What happens to the JCT and inner wall of Schlemm’s canal when IOP is high?

JCT and inner wall are pushed toward the outer wall

What happens to the JCT and inner wall of Schlemm’s canal when IOP is reduced?

JCT and inner wall move away from the outer wall

What do transient increases in IOP drive in relation to AH entry into Schlemm’s canal?

A pump motion

What are the transient increases in IOP influenced by?

Cardiac cycle, blinking, and eye movement

As IOP increases what happens due to fluid movement toward lumen of Schlemm’s canal?

Fluid pushes inner wall and trabecular meshwork toward the lumen of Schlemm’s canal

What is thought to be stalled in glaucoma regarding fluid movement?

Fluid pumping

What is the mechanism of trabecular meshwork drainage in Schlemm’s canal?

1. Formation of giant vacuoles in the endothelial cells that line Schlemm’s canal (part of the BAB)

2. Forms transcellular pores that open up toward the JCT and toward the lumen of Schlemm’s canal

3. Aqueous humor from TM flows through the giant vacuole cells

What are the two pore types that form in Schlemm’s canal?

I-pores (A) and B-pores (B)

Which pore type of Schlemm’s canal is more common?

I-pores (A)

What are I-pores (A)?

Intracellular channels that form due to Giant Vacuoles (or flat regions)

What are B-pores (B)?

Pores that form in between endothelial cells that line Schlemm’s canal

What do the pores of Schlemm’s canal do?

Mediate fluid movement into Schlemm’s canal

About how many pores per cell are in Schlemm’s canal?

~1 pore/cell

What do Schlemm’s canal cells generate pores in response to?

Cell strain

What does pore number/size directly correlate with?

IOP

What may pores of Schlemm’s canal be a mechanism of?

IOP control

When are there more/larger pores in Schlemm’s canal?

When IOP is higher

When are there less/smaller pores in Schlemm’s canal?

When IOP is lower

What is a general decreased pore number in Schlemm’s canal correlated with?

Primary open angle glaucoma

Can large particles and most cells exit the anterior chamber through the conventional route?

They cannot exit due to trabecular meshwork

Can RBCs and WBCs/immune cells exit via the conventional route of AH drainage? Why or why not?

Yes because they can be compressed/deformed and can traverse trabecular spaces and go through pores of inner wall of Schlemm’s canal

What does Aqueous pass through in the unconventional route of AH drainage?

Ciliary muscle to suprachoroidal space and sclera

How long does the circulation of aqueous via the unconventional route take?

Fluid movement into circulation takes hours (~2 hours)

How does fluid movement via the uveosceral route change with age? (recall)

Decreases with age via ECM build-up

How is the reduction of age-related uveoscleral outflow balanced?

By age related aqueous production

What is uveoscleral outflow/drainage driven by?

The difference in pressure between the anterior chamber and the suprachoroidal space (~4mmHg lower than IOP)

Why is uveoscleral outflow usually independent of IOP?

A drop/rise in IOP is usually concomitant with an identical drop/rise in suprachoroidal pressure ensuring pressure independence

What can cause a change in uveoscleral outflow in regards to IOP?

A significant drop in IOP (severe hypotony) will reduce uveoscleral outflow

What surgery can cause Cyclodialysis?

A stent placed in the angle to allow drainage to occur much faster

What is cyclodialysis?

Disruption of the connection between the ciliary muscle and the scleral spur often due to injury/surgery

What can cyclodialysis cause and how?

Can cause hypotony (IOP <6.5 mmHg) due to the formation of a direction connection between the anterior chamber and suprachoroidal space which significantly increases uveoscleral outflow

What can the increase in AH drainage to the suprachoroidal space induced by cyclodialysis lead to?

Hypotony maculopathy