Research articlePressure-induced expression changes in segmental flow regions of the human trabecular meshwork
Introduction
Glaucoma is one of the leading causes of blindness affecting over 67 million people worldwide (Quigley, 1996, Quigley, 2011). Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, and is targeted for all current glaucoma therapies. Aqueous humor flows out of the anterior chamber primarily via the conventional outflow pathway through the trabecular meshwork (TM) tissue to Schlemm’s canal (SC) and then into the episcleral venous system (Acott and Kelley, 2008, Acott et al., 2014, Brubaker, 1991). IOP is generated primarily by creating resistance to aqueous humor outflow in the TM (Johnson, 2006, Tamm, 2009). This resistance is believed to reside predominantly within the juxtacanalicular (JCT) region of the TM and the inner wall of Schlemm’s canal (Acott and Kelley, 2008, Inomata et al., 1972, Johnson et al., 1990, Overby et al., 2009).
Section snippets
Segmental outflow
Aqueous humor outflow has been shown to be segmental in nature around the circumference of the eye. Regions of relatively high, intermediate or mixed, and low flow have been demonstrated in many studies using tracers of different composition and size to visualize the outflow patterns (Buller and Johnson, 1994, Chang et al., 2014, de Kater et al., 1989, Ethier and Chan, 2001, Hann et al., 2005, Keller et al., 2011, Vranka et al., 2015). In addition, non-uniform patterns of aqueous outflow have
Extracellular matrix of the TM and IOP homeostasis
The probable primary site of outflow resistance is located within the deepest portion of the JCT and Schlemm’s canal inner wall basement membrane (Acott and Kelley, 2008, Ethier, 2002, Johnson, 2006, Stamer and Acott, 2012). The extracellular matrix (ECM) of the TM is thought to play a significant role in modulating aqueous humor outflow resistance, since modulating or disrupting it has been shown to have a direct effect on outflow resistance (Acott and Kelley, 2008, Bradley et al., 1998,
Molecular components of segmental flow
One of the goals of a newly published study was to correlate patterns of ECM gene expression with high and low flow regions of the TM in human anterior segments perfused at physiological pressure in organ culture (Vranka et al., 2015). Standard physiological flow rates were in the range of 1–9 μl/min when perfused at physiologic pressure of 8.8 mmHg, which is similar to normal physiological rate and pressure (minus episcleral venous pressure) in vivo. A number of ECM and adhesion genes were
Elevated pressure-induced effects in segmental regions of the TM
In the normal physiologic response to elevated pressure the TM undergoes ECM turnover and remodeling to correct the outflow resistance and reduce IOP (Acott et al., 2014). TM cells under mechanical stretch increased MMP14 and MMP2, while TIMP2 was decreased (Bradley et al., 2001). We previously conducted microarray gene expression studies after mechanical stretching of TM cells and identified many ECM genes that exhibited increased or decreased mRNA levels in response to stretch at varied times
Discussion
The observation of aqueous humor outflow segmentation has dramatic implications on the resistance adjustments that occur during IOP homeostasis under normal conditions, as well as during sustained pressure increases in the eye. The ECM of the JCT and SC is intricately involved in this complex process presumably through a series of steps including sensing of distortion or stretch relayed to cells triggering signaling pathways and resulting in ECM degradation and remodeling (Acott and Kelley, 2008
Disclosure
J. Vranka, none; T. Acott, none.
Acknowledgments
The authors would like to thank their funding sources: the BrightFocus Foundation (Vranka, G2014058), NIH/National Eye Institute grants EYOO3279, EY008247, EY010572 (TSA), and an unrestricted grant to the Casey Eye Institute from Research to Prevent Blindness. We would also like to thank Lions VisionGift for procuring human donor eyes.
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2022, Computer Methods and Programs in BiomedicineCitation Excerpt :Although experimental [38,68,119–123] and numerical [40,124,125] studies, as well as review articles [10,16,31,126–132], have significantly contributed to our understanding of the mechanism of outflow resistance in the conventional outflow pathway, gaps in our knowledge of outflow tissue biomechanics remain. Conventional outflow tissues are continuously subjected to a variety of static and dynamic mechanical stresses and strains that may influence their function, morphology [38,133], and outflow resistance [134]; so there is likely a coupling (fluid-structure interaction) between outflow hydrodynamics and the mechanical behavior of the TM, JCT and SC inner wall [18]. Experimental studies also showed a correlation between aqueous outflow facility and the biomechanics of the outflow connective tissues [38,39], implying that the conventional outflow resistance is actively regulated.