Pharmacologic Trabeculocanalotomy

Kaufman, Paul L.

doi:10.1001/archopht.1992.01080130036022

Cited by 17 publications

(8 citation statements)

References 28 publications

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“…However, dual signaling via these two integrins may serve to control the adhesive strength and hence contractility of the HTM cells. Contractility of the actin cytoskeleton plays an important role in mediating the movement of aqueous humor through the anterior chamber of the human eye (21)(22)(23)(24)(25). At low levels of adhesiveness, weakly attached cells may not generate sufficient force to promote contraction of the trabecular meshwork and enhance movement of aqueous humor.…”

Section: Discussionmentioning

confidence: 99%

“…The cytoskeletal organization and adhesive forces of these cells play a key role in maintaining intraocular pressure. Chemical agents that disrupt the cytoskeleton or the signaling pathways that maintain the actomyosin network, such as H-7, cytochalasins, and latrunculins, cause a decrease in intraocular pressure (21)(22)(23)(24)(25). Therefore, understanding the signaling pathways that regulate these processes is critical for understanding the mechanisms by which intraocular pressure is maintained.…”

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confidence: 99%

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Heparin II Domain of Fibronectin Uses α4β1 Integrin to Control Focal Adhesion and Stress Fiber Formation, Independent of Syndecan-4

Peterson

Sheibani

Gourichon

et al. 2005

Journal of Biological Chemistry

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Co-signaling events between integrins and cell surface proteoglycans play a critical role in the organization of the cytoskeleton and adhesion forces of cells. These processes, which appear to be responsible for maintaining intraocular pressure in the human eye, involve a novel cooperative co-signaling pathway between ␣5␤1 and ␣4␤1 integrins and are independent of heparan sulfate proteoglycans. Human trabecular meshwork cells isolated from the eye were plated on type III 7-10 repeats of fibronectin (␣5␤1 ligand) in the absence or presence of the heparin (Hep) II domain of fibronectin. In the absence of the Hep II domain, cells had a bipolar morphology with few focal adhesions and stress fibers. The addition of the Hep II domain increased cell spreading and the numbers of focal adhesions and stress fibers. Cell spreading and stress fiber formation were not mediated by heparan sulfate proteoglycans because treatment with chlorate, heparinase, or soluble heparin did not prevent Hep II domain-mediated cell spreading. Cell spreading and stress fiber formation were mediated by ␣4␤1 integrin because soluble anti-␣4 integrin antibodies inhibited Hep II domain-mediated cell spreading and soluble vascular cell adhesion molecule-1 (␣4␤1 ligand)-induced cell spreading. This is the first demonstration of the Hep II domain mediating cell spreading and stress fiber formation through ␣4␤1 integrin. This novel pathway demonstrates a cooperative, rather than antagonistic, role between ␣5␤1 and ␣4␤1 integrins and suggests that interactions between the Hep II domain and ␣4␤1 integrin could modulate the strength of cytoskeletonmediated processes in the trabecular meshwork of the human eye.Adhesive interactions between cells and extracellular matrix molecules form highly specific yet very diverse signaling conduits that regulate a wide variety of biological processes associated with cell morphology, proliferation, differentiation, migration, and survival (1-5). These adhesive events are mediated mainly by the integrin family of receptors and lead to the formation of dynamic multi-molecular structures called focal adhesions, focal complexes, and fibrillar adhesions (6, 7).The formation of focal contacts often depends on co-signaling events between integrins and cell surface proteoglycans. In fibroblasts and A375-SM melanoma cells plated on fibronectin, cooperative signaling between ␣5␤1 integrin and syndecan-4, a cell surface heparan sulfate proteoglycan (HSPG), 1 is needed to promote the formation of focal adhesions and stress fibers (8, 9). If fibronectin-null fibroblasts are plated on anti-␤1 integrin antibodies or the RGD cell binding domain of fibronectin, cells bind but do not assemble the actin cytoskeleton. However, if soluble antibody directed against the ectodomain of syndecan-4 is added, the cells will assemble focal adhesions and stress fibers (10). A similar scenario has been documented for ␣4␤1 integrin and cell surface chondroitin sulfate proteoglycans, supporting the idea that co-engagement of integrins and proteogylca...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heparin II Domain of Fibronectin Uses α4β1 Integrin to Control Focal Adhesion and Stress Fiber Formation, Independent of Syndecan-4

Peterson

Sheibani

Gourichon

et al. 2005

Journal of Biological Chemistry

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“…This might decrease trabecular outflow resistance for a long time, since reaccumulation of the pathologic resistance-increasing ECM might also need many years [78]. However, since the excess or pathologic ECM is not the only factor that increases trabecular outflow resistance and the cytoskeletal changes induced by cytoskeleton-modulating agents are reversible, such a ‘pharmacologic trabeculocanalotomy’ may not be achieved by simply using those agents.…”

Section: Future Studies Of the Tm-selective Outflow Enhancers And Gene mentioning

confidence: 99%

Comparisons of actin filament disruptors and Rho kinase inhibitors as potential antiglaucoma medications

Tian

Kaufman

2012

Expert Review of Ophthalmology

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Dynamics of the actin cytoskeleton in the trabecular meshwork play a crucial role in the regulation of trabecular outflow resistance. The actin filament disruptors and Rho kinase inhibitors affect the dynamics of the actomyosin system by either disrupting the actin filaments or inhibiting the Rho kinase-activated cellular contractility. Both approaches induce similar morphological changes and resistance decreases in the trabecular outflow pathway, and thus both have potential as antiglaucoma medications. Although the drugs might induce detrimental changes in the cornea following topical administration, lower drug concentrations in larger volumes as used clinically, but not higher drug concentrations in smaller volumes as used experimentally, could minimize corneal toxicity. Additionally, developments of trabecular meshwork-specific actin filament disruptors or Rho kinase inhibitors, prodrugs and new drug-delivery methods might avoid the drugs’ toxicity to the cornea. Gene therapies with cytoskeleton-modulating proteins may mimic the effects of the cytoskeleton-modulating agents and have the potential to permanently decrease trabecular outflow resistance.

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“…The first one includes the alteration in activities or behavior of TM cells [6]. Some agents affect cell volume and shape and loosen cell-to-cell junction and/or cell-to-extracellular matrix adhesion within the TM and inner wall of Schlemm's canal.…”

Section: Introductionmentioning

confidence: 99%

New Therapeutic Targets for Intraocular Pressure Lowering

et al. 2013

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Primary open-angle glaucoma (POAG) is a leading cause of irreversible and preventable blindness and ocular hypertension is the strongest known risk factor. With current classes of drugs, management of the disease focuses on lowering intraocular pressure (IOP). Despite of their use to modify the course of the disease, none of the current medications for POAG is able to reduce the IOP by more than 25%–30%. Also, some glaucoma patients show disease progression despite of the therapeutics. This paper examines the new described physiological targets for reducing the IOP. The main cause of elevated IOP in POAG is thought to be an increased outflow resistance via the pressure-dependent trabecular outflow system, so there is a crescent interest in increasing trabecular meshwork outflow by extracellular matrix remodeling and/or by modulation of contractility/TM cytoskeleton disruption. Modulation of new agents that act mainly on trabecular meshwork outflow may be the future hypotensive treatment for glaucoma patients. There are also other agents in which modulation may decrease aqueous humour production or increase uveoscleral outflow by different mechanisms from those drugs available for glaucoma treatment. Recently, a role for the ghrelin-GHSR system in the pathophysiology modulation of the anterior segment, particularly regarding glaucoma, has been proposed.

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Pharmacologic Trabeculocanalotomy

Cited by 17 publications

References 28 publications

Heparin II Domain of Fibronectin Uses α4β1 Integrin to Control Focal Adhesion and Stress Fiber Formation, Independent of Syndecan-4

Heparin II Domain of Fibronectin Uses α4β1 Integrin to Control Focal Adhesion and Stress Fiber Formation, Independent of Syndecan-4

Comparisons of actin filament disruptors and Rho kinase inhibitors as potential antiglaucoma medications

New Therapeutic Targets for Intraocular Pressure Lowering

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