The role of the actomyosin system in regulating trabecular fluid outflow

Abstract

Abnormally high resistance to aqueous humor drainage via the trabecular meshwork and Schlemm's canal is highly correlated with the development of primary open-angle glaucoma. Contractility of the actomyosin system in the trabecular cells or inner wall endothelium of Schlemm's canal is an important factor in the regulation of outflow resistance. Cytoskeletal agents, affecting F-actin integrity or actomyosin contractility, or gene therapies, employing overexpression of caldesmon or Rho-A inhibition, can decrease outflow resistance in the drainage pathway. In this review, we discuss the mechanisms underlying these and similar effects on trabecular outflow resistance in living animals and/or in cultured ocular anterior segments from enucleated animal or human eyes.

Introduction

The trabecular meshwork (TM) consists of arrays of collagen beams covered by endothelial-like cells, with loose extracellular matrix (ECM) occupying the spaces between the cells of the adjacent beams. The outermost juxtacanalicular (JXT) or cribriform region has no collagenous beams, but rather several cell layers immersed in a loose web of ECM fibrils. The adjacent Schlemm's canal is a continuous endothelium-lined channel that drains aqueous humor to the general venous circulation (Lütjen-Drecoll et al., 1981, Rohen et al., 1981). TM structure and experimental flow studies suggest that flow resistance is maximal in the JXT region and/or the inner wall of Schlemm's canal, although the exact location of the major resistance barrier is not clear (Johnson, 2006). Glaucoma is a progressive optic neuropathy commonly associated with elevated intraocular pressure (IOP) consequent to abnormally high resistance to aqueous humor drainage via the TM and Schlemm's canal. Glaucomatous eyes exhibit fewer TM cells and abnormally appearing JXT ECM compared to the eyes of age-matched normal individuals (Lütjen-Drecoll et al., 1981, Rohen et al., 1981), suggesting that cells and ECM in the JXT region may be critical in resistance regulation.

The actomyosin system, composed of actin microfilaments and associated proteins, is present in essentially all cells, and is highly organized in TM and Schlemm's canal cells. There are numerous microfilament-based structures in cells along the trabecular outflow pathway. These structures primarily include focal contacts, adherens cell–cell junctions, and bundles of microfilaments (Geiger et al., 1995). Filamentous actin is the major component of microfilaments, but other actin-associated proteins modulate its organization. Additionally, a physiologically contracted state of the JXT-Schlemm's canal region is required to maintain the microfilament-related structures in the outflow pathway. Microfilaments are involved in a variety of cellular processes from cell adhesion and motility to organelle traffic to adhesion-mediated signal transduction. Therefore, dynamics of the actomyosin system play important roles in changes in cell shape, volume, contractility, and adhesion to neighboring cells and to the ECM. These changes in TM and/or Schlemm's canal cells, which could affect trabecular outflow resistance by altering the dimensions or direction of flow pathways and the amount and composition of the ECM, can be modulated directly by actin-disrupting agents or indirectly by inhibition of specific protein kinase(s) or cellular contractility through administration of protein kinase inhibitors or gene therapy. In this review, we discuss the effects of pharmacological and genetic perturbation of the actomyosin system in TM and Schlemm's canal cells on trabecular outflow resistance.