Endothelia of Schlemm's canal and trabecular meshwork: distinct molecular, functional, and anatomic features

Alvarado, Jorge A.; Betanzos, Abigail; Franse-Carman, L; Chen, Janet; González‐Mariscal, Lorenza

doi:10.1152/ajpcell.00108.2003

Cited by 76 publications

(80 citation statements)

References 36 publications

(64 reference statements)

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“…Distinct differences in cell morphology are also seen depending on the perfusion direction (Alvarado et al, 2004). However, the cellular morphology of these systems do not yet match what is found physiologically.…”

Section: Future Workmentioning

confidence: 80%

“…However, the cellular morphology of these systems do not yet match what is found physiologically. These in vitro cell layers show large (micro-sized) intercellular gaps (Underwood et al, 1999;Alvarado et al, 2004) that are not seen physiologically. The permeability of vascular monolayers are reported to be 10-100 times greater than for intact endothelia, presumably due to such defects (Albelda et al, 1988;Sill et al, 1992).…”

Section: Future Workmentioning

confidence: 99%

“…This was likely due to the relatively high pressure drop they used in their system (5 mmHg), which matches the pressure drop of the aqueous outflow pathway, but, as mentioned above, is likely significantly larger than the physiological pressure drop across the inner wall endothelium. Whereas live and enucleated eyes can be perfused with pressure drops as high as 30 mmHg with relatively normal appearance of the inner wall endothelium (Johnstone and Grant, 1973;Lee and Grierson, 1975), this does not appear to be possible in Schlemm's canal cell cultures perfused in the basal to apical direction (Alvarado et al, 2004).…”

Section: Future Workmentioning

confidence: 99%

“…Recent results using these models have providing interesting findings, demonstrating that the hydraulic conductivity of these cells can change depending on whether the cells are perfused from the apical or basal side (Alvarado et al, 2004). Distinct differences in cell morphology are also seen depending on the perfusion direction (Alvarado et al, 2004).…”

Section: Future Workmentioning

confidence: 99%

“…The permeability of vascular monolayers are reported to be 10-100 times greater than for intact endothelia, presumably due to such defects (Albelda et al, 1988;Sill et al, 1992). Formation of large blebbing structures in the cells have also been seen when these cellular layers are perfused from the basal to apical direction (Alvarado et al, 2004), but these structures are different in size and morphological characteristics from giant vacuoles that are seen in Schlemm's canal cells from intact tissues (Bill, 1970;Johnstone and Grant, 1973;Ethier, 2002). Nonetheless, these studies provide the first glimpses at how these cells deal with a unique physiological stress environment.…”

Section: Future Workmentioning

confidence: 99%

See 4 more Smart Citations

‘What controls aqueous humour outflow resistance?’

Johnson

2006

Experimental Eye Research

408

366

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The bulk of aqueous humour outflow resistance is generated in or near the inner wall endothelium of Schlemm's canal in normal eyes, and probably also in glaucomatous eyes. Fluid flow through this region is controlled by the location of the giant vacuoles and pores found in cells of the endothelium of Schlemm's canal, but the flow resistance itself is more likely generated either in the extracellular matrix of the juxtacanalicular connective tissue or the basement membrane of Schlemm's canal. Future studies utilizing in vitro perfusion studies of inner wall endothelial cells may give insights into the process by which vacuoles and pores form in this unique endothelium and why inner wall pore density is greatly reduced in glaucoma. Keywordsglaucoma; Schlemm's canal; hydraulic conductivity It has been recognized for more that 130 years that the elevated pressure characteristic of primary open-angle glaucoma arises due to an increased resistance to the outflow of aqueous humour from the eye. (Leber, 1873) However, a conclusive determination of where in the outflow pathways this elevated outflow resistance is generated has been elusive. Surprisingly, the locus of aqueous humour outflow resistance in the normal eye has also been not been unequivocally determined.Seidel (1921) using light microscopy, stated 'that the inner wall of Schlemm's canal stand in open communication with the anterior chamber, and that the aqueous humour directly washes around the inner wall endothelium of Schlemm's canal and is only separated from the lumen of Schlemm's canal by a thin, outer membrane'. Our view is little different today. The locus of outflow resistance, both in the normal eye and the glaucomatous eye, is thought to arise either in the endothelial lining of Schlemm's canal, or very near to this location. In this article, current thoughts on where that flow resistance might be generated are reviewed.There are a number of excellent review articles (Tripathi, 1974a,b;Bill, 1975;Bill and Mäepea, 1994;Gong et al., 1996;Johnson and Erickson, 2000;Ethier, 2002) that describe the detailed morphology and physiology of the aqueous outflow pathway. In this review, the evidence that leads to the conclusion that the inner wall region is responsible for the bulk of aqueous humour outflow resistance is first presented. Then, attention is focused on those proximal aspects of this pathway that are nearest to the endothelial linings of Schlemm's canal, and the transport characteristics of these structures.The bulk of the aqueous humour flows out of the anterior chamber of the eye through the conventional aqueous outflow pathway comprised of the trabecular meshwork, the juxtacanalicular connective tissue, the endothelial lining of Schlemm's canal, Schlemm's canal itself, the collecting channels and aqueous veins, and then finally drains into the episcleral NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript venous system, rejoining the blood from whence it came (in this review, the juxtacanalicular...

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Section: Future Workmentioning

confidence: 80%

Section: Future Workmentioning

confidence: 99%

Section: Future Workmentioning

confidence: 99%

Section: Future Workmentioning

confidence: 99%

Section: Future Workmentioning

confidence: 99%

See 3 more Smart Citations

‘What controls aqueous humour outflow resistance?’

Johnson

2006

Experimental Eye Research

408

366

View full text Add to dashboard Cite

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Recreating a human trabecular meshwork outflow system on microfabricated porous structures

Torrejon

Bergkvist

et al. 2013

Biotech & Bioengineering

102

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Glaucoma is the leading cause of irreversible blindness, resulting from an increase in intraocular pressure (IOP). IOP is the only modifiable risk factor of glaucoma and is controlled by the outflow of the aqueous humor through the human trabecular meshwork (HTM). Currently, the lack of a proper in vitro HTM model impedes advances in understanding outflow physiology and discovering effective IOP-lowering anti-glaucoma therapeutics. Therefore, we designed and constructed an in vitro HTM model using micropatterned, porous SU-8 scaffolds, which support cells to recapitulate functional HTM morphology and allow the study of outflow physiology. The pore size of SU-8 scaffolds, surface coating, cell seeding density, and culture duration were evaluated for HTM cell growth. The bioengineered HTM was characterized by F-actin staining and immunocytochemistry of HTM markers. A stand-alone perfusion chamber with an integrated pressure sensing system was further constructed and used for the investigation of the outflow facility of the bioengineered HTM treated with latrunculin B-an IOP lowering agent. Cells in the in vitro model exhibited HTM-like morphology, expression of α-smooth muscle actin, myocilin, and αß-crystallin, outflow characteristics and drug responsiveness. Altogether, we have developed an in vitro HTM model system for understanding HTM cell biology and screening of pharmacological or biological agents that affect trabecular outflow facility, expediting discovery of IOP-lowering, anti-glaucoma therapeutics.

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Regulation of Plasticity and Fibrogenic Activity of Trabecular Meshwork Cells by Rho GTPase Signaling

2014

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Glaucoma, a prevalent blinding disease is commonly associated with increased intraocular pressure due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM). Although increased TM tissue contraction and stiffness in association with accumulation of extracellular matrix (ECM) are believed to be partly responsible for increased resistance to AH outflow, the extracellular cues and intracellular mechanisms regulating TM cell contraction and ECM production are not well defined. This study tested the hypothesis that sustained activation of Rho GTPase signaling induced by lysophosphatidic acid (LPA), TGF-β and connective tissue growth factor (CTGF) influences TM cell plasticity and fibrogenic activity which may eventually impact resistance to AH outflow. Various experiments performed using human TM cells revealed that constitutively active RhoA (RhoAV14), TGF-β2, LPA and CTGF significantly increase the levels and expression of Fibroblast Specific Protein-1 (FSP-1), α-smooth muscle actin (αSMA), collagen-1A1 and secretory total collagen, as determined by q-RT-PCR, immunofluorescence, immunoblot, flow cytometry and the Sircol assay. Significantly, these changes appear to be mediated by Serum Response Factor (SRF), myocardin-related transcription factor (MRTF-A), Slug and Twist-1, which are transcriptional regulators known to control cell plasticity, myofibroblast generation/activation and fibrogenic activity. Additionally, the Rho kinase inhibitor-Y27632 and anti-fibrotic agent-pirfenidone were both found to suppress the TGF-β2-induced expression of αSMA, FSP-1 and collagen-1A1. Taken together, these observations demonstrate the significance of RhoA/Rho kinase signaling in regulation of TM cell plasticity, fibrogenic activity and myofibroblast activation, events with potential implications for the pathobiology of elevated intraocular pressure in glaucoma patients.

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Endothelia of Schlemm's canal and trabecular meshwork: distinct molecular, functional, and anatomic features

Cited by 76 publications

References 36 publications

‘What controls aqueous humour outflow resistance?’

‘What controls aqueous humour outflow resistance?’

Recreating a human trabecular meshwork outflow system on microfabricated porous structures

Regulation of Plasticity and Fibrogenic Activity of Trabecular Meshwork Cells by Rho GTPase Signaling

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