Biomechanics of Schlemm's Canal Endothelial Cells: Influence on F-Actin Architecture

Ethier, C. Ross; Read, A. Thomas; Chan, Darren

doi:10.1529/biophysj.103.038133

Cited by 93 publications

(80 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[25][26][27][28][29] This appears to be primarily due to large changes in the physical conformation of the outflow pathway, where the JCT/SC distends far out into and obstructs the SC. [26][27][28]30 Images in some of these studies show dramatic partial or total collapse of the SC, which nearly or actually occludes the canal further obstructing lateral circumferential flow and may completely block fluid egress into collector channels. [25][26][27]29 At higher pressures, particularly when sustained as in glaucoma, the JCT/ SC forms actual herniations out into the collector channels.…”

Section: Figmentioning

confidence: 98%

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Acott

Kelley

Keller

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

152

150

View full text Add to dashboard Cite

Although glaucoma is a relatively common blinding disease, most people do not develop glaucoma. A robust intraocular pressure (IOP) homeostatic mechanism keeps ocular pressures within relatively narrow acceptable bounds throughout most peoples' lives. The trabecular meshwork and/or Schlemm's canal inner wall cells respond to sustained IOP elevation and adjust the aqueous humor outflow resistance to restore IOP to acceptable levels. It appears that the cells sense IOP elevations as mechanical stretch or distortion of the actual outflow resistance and respond by initiating a complex extracellular matrix (ECM) turnover process that takes several days to complete. Although considerable information pertinent to this process is available, many aspects of the IOP homeostatic process remain to be elucidated. Components and mechanisms beyond ECM turnover could also be relevant to IOP homeostasis, but will not be addressed in detail here. Known aspects of the IOP homeostasis process as well as possible ways that it might function and impact glaucoma are discussed. Glaucoma Glaucoma is an optic neuropathy characterized by a distinctive pattern of permanent visual field loss. 1,2Optic disk cupping is also a diagnostic parameter. Elevated intraocular pressure (IOP) is the primary risk factor for glaucomatous optic nerve damage and reducing pressure remains the only treatable component of disease progression.2,3 Although glaucoma is a relatively common blinding disease affecting over 67 million persons worldwide, [3][4][5] it is noteworthy that only 2%-8% of people actually develop this disease within their lifetime and most only at advanced ages. The implication of this observation is that some very efficacious mechanism exists to maintain IOP within acceptable ranges throughout the life of most people. 6Intraocular Pressure IOP is maintained primarily by changes in the aqueous humor outflow resistance, which is thought to reside predominantly within the cribriform or juxtacanalicular ( JCT) region of the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC).6-10 Aqueous humor inflow rates are relatively stable and are not pressure dependent, until very high pressures are achieved. 11,12 Although outflow through the alternative or uveoscleral pathway is clearly important, most of the outflow in humans is through the conventional TM/SC route. 2,7,8,12,13 IOP HomeostasisFor our purposes, in this study, we will define IOP homeostasis as corrective adjustments of the aqueous humor outflow resistance, which occur in direct response to sustained pressure changes and which maintain IOP within acceptable physiological ranges.We hypothesize that the flow resistance within the conventional outflow pathway is continually being adjusted with time frames measured in many hours and that sustained pressure changes serve as a guide for the direction and extent of homeostatic resistance modifications. Since the outflow resistance is thought to be comprised primarily of extracellular matrix (ECM) 6,7,9,10,14,15 and sinc...

show abstract

Section: Figmentioning

confidence: 98%

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Acott

Kelley

Keller

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

152

150

View full text Add to dashboard Cite

show abstract

“…(Grant 1956;Grant 1958;Grant 1963;Buller and Johnson 1994;Parc et al 2000;Ethier and Chan 2001;Gottanka et al 2001;Hann et al 2005;Hann and Johnson 2007) TM dissections studies and other observations suggest that fluid may not be free to move around the circumference of SC. (Hogan et al 1971;Rosenquist et al 1989;Lutjen-Drecoll 1999;Ethier 2002;Ethier et al 2004;Johnstone 2004;Johnson 2006) Clinical observations that multiple site trabeculectomy or stent placement improves drainage, further highlight this phenomenon. Evaluation of F-actin cytoskeletal alignments within SC inner and outer wall endothelial cells and shear stress modeling of radial flow in SC, particularly relative to collector channels, suggests that this is more complicated than originally perceived.…”

Section: Segmental Flowmentioning

confidence: 99%

“…Evaluation of F-actin cytoskeletal alignments within SC inner and outer wall endothelial cells and shear stress modeling of radial flow in SC, particularly relative to collector channels, suggests that this is more complicated than originally perceived. (Ethier et al 2004) Possible sources of outflow resistance Glycosaminoglycans (GAGs) within the TM have long been a favorite hypothetical source of the outflow resistance. (Bárány 1953;Pedler 1956;Francois 1975) These long repeat disaccharide chains with a high density of carboxyl and sulfate groups, which are negatively charged at physiologic pH, would be the ideal material to form the outflow resistance.…”

Section: Segmental Flowmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

424

443

View full text Add to dashboard Cite

The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

show abstract

“…9,10 The endothelial cells of the inner wall of SC are important in regulating outflow resistance and thus IOP. 11,12 Nitric oxide (NO) regulation appears to have a role in POAG. Family association studies [13][14][15] show a relationship between NOS3 gene polymorphisms, which encode for endothelial NO synthase (eNOS), and POAG.…”

mentioning

confidence: 99%

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Lei

Stamer

et al. 2014

Investigative Ophthalmology & Visual Science

View full text Add to dashboard Cite

Citation: Lei Y, Stamer WD, Wu J, Sun X. Endothelial nitric oxide synthaserelated mechanotransduction changes in aged porcine angular aqueous plexus cells. Invest Ophthalmol Vis Sci. 2014;55:8402-8408. DOI: 10.1167/iovs.14-14992 PURPOSE. To investigate effects of aging on endothelial nitric oxide synthase (eNOS) expression and signaling in angular aqueous plexus (AAP) (functional equivalent to human Schlemm's canal) cells subjected to shear stress. METHODS.The AAP cells were isolated differentially from porcine outflow tissues using puromycin selection. Cell aging was induced by culturing cells in hyperoxia condition (40% oxygen and 5% carbon dioxide) for 14 days. The AAP cells grown in chamber slides were exposed to a shear stress of 8 dynes/cm 2 for 24 hours. Expression of eNOS, eNOS-phospho Thr495, eNOS-phospho Ser1177, and Akt-phospho was tested by Western blot analysis and immunofluorescence staining. Nitric oxide (NO) levels were measured using the Griess assay. RESULTS.Compared with control, eNOS levels in aged cells were significantly reduced by 60% (P < 0.05; n ¼ 6). Phosphorylation of eNOS at Ser1177 and Akt at Ser473 was 63% and 80% lower in aged cells, respectively, whereas phosphorylation of the eNOS inhibition site (Thr495) increased by 6.1-fold (P < 0.05; n ¼ 6). Shear stress (8 dynes/cm 2 for 24 hours) increased eNOS abundance (total protein and at cell borders) and phosphorylation at Ser1177 by 1.7-fold and 1.8-fold, respectively (P < 0.05; n ¼ 6), whereas aged cells were unresponsive. In control cells exposed to shear stress, the NO concentration was 1.8-fold higher than in the static group (P < 0.05; n ¼ 4); however, aged cells were unresponsive to shear stress (mean 6 SD, 4.3 6 1.3 vs. 4.1 6 1.4 lM).CONCLUSIONS. Aged AAP cells appear compromised in their mechanotransduction machinery involving eNOS, the protein product of the gene, NOS3, polymorphisms of which impart a risk for the development of glaucoma.Keywords: aging, Schlemm's canal, eNOS G laucoma comprises a group of complex and heterogeneous blinding diseases, affecting almost 60 million people worldwide. 1 Clinically, glaucoma is characterized by cupping of the optic nerve head and visual field loss. Elevated IOP is the primary risk factor for glaucomatous optic nerve damage, and reducing pressure remains the only treatable end point that slows or stops disease progression. The risk of developing POAG also clearly increases with age. 2-8 Primarily, IOP is determined by changes in aqueous humor outflow resistance, which is thought to reside mainly in the juxtacanalicular region, where the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC) cells interact. 9,10 The endothelial cells of the inner wall of SC are important in regulating outflow resistance and thus IOP. 11,12Nitric oxide (NO) regulation appears to have a role in POAG. Family association studies [13][14][15] show a relationship between NOS3 gene polymorphisms, which encode for endothelial NO synthase (eNOS), and POAG. These recent findings are consistent wit...

show abstract

Biomechanics of Schlemm's Canal Endothelial Cells: Influence on F-Actin Architecture

Cited by 93 publications

References 24 publications

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Extracellular matrix in the trabecular meshwork

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Contact Info

Product

Resources

About