Direct return of another extravascular fluid, lymph, to the venous system is by means of an extrinsic pumping mechanism involving valves76 rather than intracellular or transcellular pores. Venous blood returns through an extrinsic pumping mechanism77,78 involving valves. Cerebrospinal fluid returns directly to the vascular system via valves in the model of Welsh.79 Aqueous returns directly to the venous system in the canine eye as demonstrated by Van Buskirk80 (Fig. 16).
Laboratory evidence of pressure-sensitive TM tissues and SC valves, coupled with clinical knowledge of constant pressure gradient changes within the eye predicts pump-like behavior of the outflow system. Identification of in vivo correlates provides a measure of the robustness of the laboratory-derived aqueous outflow pump model. A recent search of the literature related to pulsatile flow in aqueous veins provides evidence consistent with the prediction of an aqueous outflow pump mechanism, as does recent clinical evidence of pulsatile flow into collector channels and SC.
Pulse wave origination from an aqueous source rather from episcleral venous pulsation is clear from the character of the rapidly moving aqueous pulse wave. The aqueous pulse wave starts at the entrance of the emissary aqueous vessels in the sclera and displaces the slower moving blood in the mixing vessels as it advances.89 Influx of aqueous resulting from the moving aqueous wave front in systole occurs more rapidly than the influx of blood during diastole.89 Compression of recipient episcleral veins, which precludes a retrograde venous pulse, causes an increase in pulsations.81,83,84 Furthermore, a complex pulsatile parabolic wave of aqueous originates at the aqueous vein scleral emissary. The complex parabolic wave propagates in aqueous and mixing veins at the same time movement of blood in adjacent episcleral veins is much slower and pulsatile behavior is absent. Compression of the homolateral carotid artery causes arrest of pulsations.90 Enhanced pulsatile aqueous discharge results from increasing IOP caused by pressure on the eye83,84 or water drinking92 (Fig. 17).
Stegmann uses an operating room microscope with 80-power magnification and high-resolution videographic capability to document his microsurgery techniques.63 Gonioscopically, he observes pulsatile aqueous flow into collector channels92 by compressing episcleral veins with the flange of a goniolens to cause slight blood reflux into collector channels; aqueous in the collector channels is blood-tinged permitting visualization of aqueous movement. Synchrony of pulsations with the cardiac pulse is evident because head movement and associated image movement is apparent with each cardiac cycle.
The origin of the aqueous column in SC is a clear funnel of aqueous originating proximally with a base at the level of the posterior TM just above the scleral spur. The funnel apex extends upward toward Schwalbe’s line. The funnel of aqueous is continuous with a more distal clear cylindrical area that curves so that a portion of the cylinder runs circumferentially in SC. The recurring pattern of aqueous ejection into SC originates from the distal cylindrical area. The same phenomenon occurs consistently in the 30 cardiac cycles recorded. The salient features are present at each cycle, with the appearance varying slightly from cycle to cycle, never appearing exactly the same.
The sequence of aqueous propulsion originates when the funnel of aqueous enlarges rapidly with enlargement progressing from base to apex. Following complete filling the funnel becomes progressively smaller beginning at the base and progressing to the apex; the clear funnel of aqueous completely collapses during some cycles. As the funnel-shaped area becomes smaller during diastole the more distal cylindrical area progressively enlarges with the enlargement starting at the apex of the funnel creating the appearance of a pulse wave of aqueous progressively entering the cylindrical region from the funnel.
The cylindrical area containing aqueous enlarges in a progressive fashion beginning proximally at the apex of the funnel until the cylindrical area achieves the appearance of a complete column. Reduction in size of the cylindrical area starts proximally at the apex of the funnel before enlargement of the distal cylindrical area is completed. Progressive reduction in size of the aqueous containing cylinder from the proximal to distal region culminates in the ejection of aqueous into the blood-filled SC. The cylindrical region collapses at completion of the ejection phase.
Aqueous is constrained to a specific path as it flows into SC in a propulsive wave. The funnel-shaped and cylindrical areas define a lumen that changes shape in synchrony with the cardiac cycle. The constraining structures appear highly compliant because the funnel-shaped and cylindrical areas rapidly undergo a change in shape in response to IOP transients. The pattern of flow suggests that the structural tissues guiding flow accommodate or aid in causing the propulsive wave. The size, shape, and movement of aqueous through the structures are consistent with behavior predicted from the laboratory characterization of SC valve geometry7,66 and responses of both SCE8,21,26 and SC valves7,23,24,66,93,94 to tissue loading induced by pressure gradient changes.
The proposed mechanism is based first on consideration of laboratory evidence of tissue geometry, tissue composition, tissue loading responses, and tracer studies. Second, the laboratory evidence is correlated with in vivo evidence of pulsatile flow into aqueous veins from collector channels, into collector channels from SC, and into SC from the AC. Third, a series of animations depict various scenarios of tissue movement and aqueous flow patterns during systole and diastole92 that place constraints on possible alternatives.
During diastole, IOP decreases and the IOP-induced pressure load on SCE and the trabecular lamellae also decreases. Elastic energy stored in the trabecular tissues during systole induces elastic recoil in diastole. Continuing recoil of the trabecular lamellae and SCE reduces SC pressure causing aqueous to enter SC from SC valves, representing a form of diastolic “suction”. In this model, the pressure gradient across SCE need not be large. Because elastic recoil of the TM causes diastolic filling of SC from SC valves, at the initiation of the next systole the end diastolic volume of SC is sufficiently large that pressure gradients across SCE are small or absent. Accordingly, during the next systole, the outward movement of SCE caused by the systolic IOP increase also causes a corresponding increase in SC pressure, effectively pushing fluid out of the canal without requiring a large pressure gradient across the wall of SCE. Similarly, SC valve transmural pressure gradients are modest due to the Starling resistor effect in a collapsible tube connected to 2 reservoirs and enclosed in a chamber with changing pressures.15,96,97
Relationships of tension to length and stress to stretch are common to many soft tissues, are prevalent throughout the cardiovascular system,13 and are present in the aqueous outflow system.98 In this aqueous outflow model, at the homeostatic IOP setpoint, trabecular tissue distention is at the lower end of its length-tension curve. Systole induces modest additional tension and correspondingly with a fall in IOP during diastole, modest recoil occurs leading to limited SC filling. If IOP rises beyond the homeostatic setpoint, the trabecular tissues move up the length-tension curve. A rise in IOP during systole induces greater tension. The resulting recoil during diastole is more forceful increasing the aqueous volume entering SC. During the next systole, additional aqueous is discharged from SC thus increasing stroke volume. The increased stroke volume in turn reduces IOP, returning the trabecular tissues to their homeostatic length-tension relationship92 (Fig. 17).
Aqueous entry to the AC and egress from the AC to SC occurs down a pressure gradient set up by the heart. Principles of cardiac hydrodynamic tissue loading followed by recoil of elastic elements is a physiologic mechanism extensively employed throughout the cardiovascular system.13,78,99 Tissue loading and recoil begins in the heart where ventricular filling during diastole is initially rapid because the ventricle produces a diastolic “suction” as the extracellular elements of the myocardium recoil elastically from their contracted systolic configuration.13,78,99 A feature of the large elastic arteries is that the stretch during systole results in elastic recoil during diastole augmenting the smooth flow of blood.13,78,99 Left coronary artery flow occurs primarily during diastole due to the elastic recoil of the systolic pressure-distended aorta.13,78,99 Skeletal muscle contraction followed by elastic recoil of extracellular elements of the contiguous muscles and vein wall creates a diastolic suction driving the skeletal muscle pump in veins.78,99 Similarly, non-muscular lymphatic vessels are in series with the muscular vessels permitting extrinsic propulsion of lymph in which pumping is associated with recoil of the vessel walls in response to changing pressure transients.78 End diastolic volume and stretch regulate stroke volume in the larger lymphatics, thus linking stroke volume to pressure in the lumen.78
Intrinsic regulation of vascular wall structure is the primary mechanism optimizing vascular wall stress to control pressure and flow. Extrinsic forces such as neural and hormonal factors then secondarily augment pressure and flow regulation. Through biomechanical coupling or mechanotransduction, cells alter their functional characteristics in response to externally applied loads.18 The first systematic tissue-loading studies of the aqueous outflow system8 demonstrated a tight biomechanical coupling between IOP and TM architecture, a coupling emphasized in subsequent reports (Fig. 4).7,23,24,66,93,94 The coupling of IOP and TM architecture led us to predict that SCE and associated resistance elements of the TM “behave functionally as a pressure-sensing and pressure-regulatory arrangement.”8 Since that time understanding of biomechanical coupling principles has led to a unifying model of intrinsic pressure and flow regulation in the vascular system.13,100 Shear and wall stresses integral to the aqueous pump model predict the presence of parallel intrinsic regulatory pathways in the aqueous outflow and vascular regulatory systems.
Pressure and flow-mediated biomechanical coupling provides a regulatory framework in the vascular system, yet in the literature of the aqueous outflow system, no analogous unifying regulatory framework has been proposed.101 The prevailing paradigm in the aqueous outflow system literature posits a sufficiently rigid syncytium of ECM material in the juxtacanalicular space to sustain a steady passive resistance that regulates both pressure and flow.5,6,102,103 The paradigm precludes biomechanical coupling because resistance resides in a syncytium of ECM material. The pressure gradient dissipates on passage through the ECM material and flow occurs across low- resistance pores in SCE.104–106 The ECM resistance paradigm precludes both meaningful tissue loading at SCE to create wall stress and insufficient flow rates to induce shear stress.101 Pore frequency in SCE markedly decreases or is absent when fixation duration is short106 (eg, 30- or 60- minute in vivo fixation duration (Fig. 12)) suggesting that pores result from fixation.106 In the aqueous outflow pump model all aqueous flow is through SC valves.
Intrinsic trabecular and vascular endothelial cell deforming forces that permit biomechanical coupling or mechanotransduction include stresses perpendicular to the wall lumen called normal or wall stress and those tangential to the lumen called shear stress, while intermediate vectors cause torsional stress.13,15,78 Force-dependent changes in cell surface receptors and cytoskeletal scaffold geometry transduce the forces into biochemical responses.44,107 Endothelial cells sense pressure and flow, transduce the flow through biomechanical linkage, and then initiate responses that effect changes in cellular and extracellular structural components of the walls of the outflow system and vasculature.13 In the aqueous pump model, wall stress, shear stress (resulting from high flow in SC valves and at their discharge sites in SC), and oscillatory stresses that induce tissue and cellular deformation are integral to function. Unifying principles of intrinsic pressure and flow regulation identified in the systemic vascular system13 predict comparable regulatory pathways in the aqueous outflow system. The presence of any such aqueous outflow system regulatory pathways strengthens the model.
The unifying pressure regulatory principle of vascular biomechanics is that vessel walls adapt to maintain a local wall shear stress set point that is a function of the optimal local transmural pressure.13,108,109 Vascular wall stress (tension/unit thickness) is similar from capillaries to the aorta.78 Vessel radius is determined by wall stress and vessel radius alterations impact both transmural pressure and flow.78 Minimizing work cost of blood transport with respect to radius has led to an evolutionarily optimized vessel radius.110,111 Shear stress resulting from flow governs lumen radius and causes adaptive changes in wall thickness, changing tissue mass and volume.13 Different energy cost functions apply depending on vessel location and function, but once differentiated to serve that function, vessels maintain constant shear stress that in turn maintains local transmural pressure relationships.78,108
This report examines evidence supporting a model of the aqueous outflow system as a mechanical pump. Laboratory evidence demonstrates the presence of valves in SC. Elastic and contractile properties of the TM and SC valves permit pressure transients to cause pulsatile fluid movement through the outflow system. Clinical evidence of pulsatile flow into SC, from SC into the collector channels, and from aqueous veins into episcleral veins supports the model. In this model alterations in the stroke volume of aqueous discharged to the episcleral veins maintain short-term homeostasis. Mechanotransduction through biomechanical coupling of IOP, flow and wall stresses optimizes tissue biomechanics resulting in long-term homeostasis.
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