Cationic Mechanosensitive Channels Mediate Trabecular Meshwork Responses to Cyclic Mechanical Stretch

Abstract

The trabecular meshwork (TM) is responsible for intraocular pressure (IOP) homeostasis in the eye. The tissue senses IOP fluctuations and dynamically adapts to the mechanical changes to either increase or decrease aqueous humor outflow. Cationic mechanosensitive channels (CMCs) have been reported to play critical roles in mediating the TM responses to mechanical forces. However, how CMCs influence TM cellular function affect aqueous humor drainage is still elusive. In this study, human TM (HTM) cells were collected from a Chinese donor and subjected to cyclically equiaxial stretching with an amplitude of 20% at 1 Hz GsMTx4, a non-selective inhibitor for CMCs, was added to investigate the proteomic changes induced by CMCs in response to mechanical stretch of HTM. Gene ontology enrichment analysis demonstrated that inhibition of CMCs significantly influenced several biochemical pathways, including store-operated calcium channel activity, microtubule cytoskeleton polarity, toll-like receptor signaling pathway, and neuron cell fate specification. Through heatmap analysis, we grouped 148 differentially expressed proteins (DEPs) into 21 clusters and focused on four specific patterns associated with Ca2+ homeostasis, autophagy, cell cycle, and cell fate. Our results indicated that they might be the critical downstream signals of CMCs adapting to mechanical forces and mediating AH outflow.

TRPV4 subserves physiological and pathological elevations in intraocular pressure

“…TM responsiveness to mechanical stress, elevated TGFb concentrations and chronic steroid treatment converge at the level of increased ECM stiffness and actomyosin contractility as Rho kinase (ROCK)-dependent increases in JCT resistance to uid ow (10,12,13). This process has been associated with upregulation of the mTOR-AKT1 pathway, SMAD2/3 transcription, autophagy (14), overactivation of integrin-based cell-ECM contacts (15), release of matrix metalloproteinases (MMPs) (16), and altered expression of TM proteins related to aging, DNA structure, cytochrome P450 signaling and cell differentiation (17) while the identity of pressure sensing molecules that drive these remodeling pathways remains poorly understood. Cultured human TM cells are highly mechanosensitive, responding to physiological (5-15 mm Hg) pressure steps with Na + , K + and Ca 2+ currents mediated by Piezo1, TRPV4 and TREK-1 channels (18-21).…”