scholarly journals Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

2021 ◽  
Vol 118 (16) ◽  
pp. e2022461118
Author(s):  
Pinkal D. Patel ◽  
Yen-Lin Chen ◽  
Ramesh B. Kasetti ◽  
Prabhavathi Maddineni ◽  
William Mayhew ◽  
...  
Keyword(s):  
Shear Stress ◽  
Intraocular Pressure ◽  
Trabecular Meshwork ◽  
Transient Receptor Potential ◽  
Vision Loss ◽  
Open Angle Glaucoma ◽  
Transient Receptor Potential Vanilloid ◽  
Flow Shear ◽  
Flow Shear Stress ◽  
Trpv4 Channel

Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca2+ entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca2+ entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm’s canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma.

scholarly journals Mechanically induced cytoskeletal remodeling in trabecular meshwork cells requires TRPV4 - Rho signaling interactions

2020 ◽  
Author(s):  
Monika Lakk ◽  
David Križaj
Keyword(s):  
Focal Adhesion ◽  
Trabecular Meshwork ◽  
Actin Polymerization ◽  
Transient Receptor Potential ◽  
Open Angle Glaucoma ◽  
Focal Adhesions ◽  
Small Gtpase ◽  
Transient Receptor Potential Vanilloid ◽  
Aqueous Humor Outflow ◽  
Membrane Stretch

AbstractIntraocular pressure (IOP) is dynamically regulated by the trabecular meshwork (TM), a mechanosensitive tissue that protects the eye from injury through dynamic regulation of aqueous humor outflow from the anterior chamber of the eye. IOP-dependent increases in TM stiffness and contractility drive open angle glaucoma but the mechanotransduction mechanisms that regulate these processes remain poorly understood. We used fluorescence imaging and biochemical analyses to investigate cytoskeletal and focal adhesion remodeling in human TM cells stimulated with cyclic strain. The cells showed enhanced F-actin polymerization, increased number and size of focal adhesions, and activation of the Rho-associated protein kinase (ROCK). Stretch-induced activation of the small GTPase RhoA, and tyrosine phosphorylations of focal adhesion proteins paxillin, focal adhesion kinase (FAK), vinculin and zyxin were time-dependently inhibited by HC-067047, an antagonist of transient receptor potential vanilloid 4 (TRPV4) channels, and the ROCK inhibitor Y-27632. TRPV4 and ROCK activation were required for zyxin translocation and increase in the number/size of focal adhesions in stretched cells. Y-27632 blocked actin polymerization without affecting calcium influx induced by membrane stretch and the TRPV4 agonist GSK1016790A. These results reveal that mechanical tuning of TM cells requires parallel activation of TRPV4, integrins and ROCK, with chronic stress leading to sustained remodeling of the cytoskeleton and focal complexes.

scholarly journals The Effect of Fluid Flow Shear Stress and Substrate Stiffness on Yes-Associated Protein (YAP) Activity and Osteogenesis in Murine Osteosarcoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3128
Author(s):  
Thomas R. Coughlin ◽  
Ali Sana ◽  
Kevin Voss ◽  
Abhilash Gadi ◽  
Upal Basu-Roy ◽  
...  
Keyword(s):  
Shear Stress ◽  
Fluid Flow ◽  
Bone Cells ◽  
Bone Cancer ◽  
Substrate Stiffness ◽  
Flow Shear ◽  
Fluid Movement ◽  
Flow Shear Stress ◽  
Fluid Flow Shear Stress ◽  
New Treatments

Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness—two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity—which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression.

Transient receptor potential vanilloid 2‐mediated shear‐stress responses in C2C12 myoblasts are regulated by serum and extracellular matrix

2015 ◽  
Vol 29 (11) ◽  
pp. 4726-4737 ◽  
Author(s):  
Felix Kurth ◽  
Alfredo Franco‐Obregón ◽  
Marco Casarosa ◽  
Simon K. Küster ◽  
Karin Wuertz‐Kozak ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Shear Stress ◽  
Stress Responses ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
C2c12 Myoblasts ◽  
Transient Receptor

Temporal gradient in shear-induced signaling pathway: involvement of MAP kinase, c-fos, and connexin43

2000 ◽  
Vol 278 (5) ◽  
pp. H1598-H1605 ◽  
Author(s):  
Xuping Bao ◽  
Craig B. Clark ◽  
John A. Frangos
Keyword(s):  
Shear Stress ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Steady Shear ◽  
Flow Shear ◽  
Temporal Gradient ◽  
Step Flow ◽  
Shear Component ◽  
Flow Shear Stress ◽  
Impulse Flow

The effect of a temporal gradient in shear and steady shear on the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/ERK2), c- fos, and connexin43 (Cx43) in human endothelial cells was investigated. Three laminar flow profiles (16 dyn/cm2), including impulse flow (shear stress abruptly applied for 3 s), ramp flow (shear stress smoothly transitioned at flow onset), and step flow (shear stress abruptly applied at flow onset) were utilized. Relative to static controls, impulse flow stimulated the phosphorylation of ERK1/ERK2 8.5- to 7.5-fold, respectively at 10 min, as well as the mRNA expression of c- fos 51-fold at 30 min, and Cx43 8-fold at 90 min. These high levels of mRNA expression were sustained for at least 4 h. In contrast, ramp flow was unable to significantly induce gene expression and even inhibited the activation of ERK1/ERK2. Step flow, which contains both a sharp temporal gradient in shear stress and a steady shear component, elicited only moderate and transient responses, indicating the distinct role of these fluid shear stimuli in endothelial signal transduction. The specific inhibitor of mitogen-activated protein kinase kinase PD-98059 inhibited impulse flow-induced c -fos and Cx43 mRNA expression. Thus these findings implicate the involvement of ERK1/ERK2, c -fos, and Cx43 in the signaling pathway induced by the temporal gradient in shear.

scholarly journals Morphological changes in the trabecular meshwork and Schlemm’s canal after treatment with topical intraocular pressure-lowering agents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-Hye Park ◽  
Hyun Woo Chung ◽  
Eun Gyu Yoon ◽  
Min Jung Ji ◽  
Chungkwon Yoo ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Trabecular Meshwork ◽  
Morphological Changes ◽  
Open Angle Glaucoma ◽  
Anterior Segment ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Before And After ◽  
Treatment Naïve ◽  
Aqueous Outflow

AbstractGlaucoma treatment is usually initiated with topical medication that lowers the intraocular pressure (IOP) by reducing the aqueous production, enhancing the aqueous outflow, or both. However, the effect of topical IOP-lowering medications on the microstructures of the aqueous outflow pathway are relatively unknown. In this retrospective, observational study, 56 treatment-naïve patients with primary open-angle glaucoma were enrolled. Images of the nasal and temporal corneoscleral limbus were obtained using anterior segment optical coherence tomography (AS-OCT). The conjunctival vessels and iris anatomy were used as landmarks to select the same limbal area scan, and the trabecular meshwork (TM) width, TM thickness, and Schlemm’s canal (SC) area were measured before and after using the IOP-lowering agents for 3 months. Among the 56 patients enrolled, 33 patients used prostaglandin (PG) analogues, and 23 patients used dorzolamide/timolol fixed combination (DTFC). After 3 months of DTFC usage, the TM width, TM thickness, and SC area did not show significant changes in either the nasal or temporal sectors. Conversely, after prostaglandin analog usage, the TM thickness significantly increased, and the SC area significantly decreased (all P < 0.01). These findings warrant a deeper investigation into their relationship to aqueous outflow through the conventional and unconventional outflow pathways after treatment with PG analogues.

scholarly journals Role of Fibronectin in Primary Open Angle Glaucoma

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1518 ◽  
Author(s):  
Jennifer A. Faralli ◽  
Mark S. Filla ◽  
Donna M. Peters
Keyword(s):  
United States ◽  
Trabecular Meshwork ◽  
Vision Loss ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
The United States ◽  
Open Angle ◽  
Cell Matrix ◽  
Fibronectin Fibrils

Primary open angle glaucoma (POAG) is the most common form of glaucoma and the 2nd most common cause of irreversible vision loss in the United States. Nearly 67 million people have the disease worldwide including >3 million in the United States. A major risk factor for POAG is an elevation in intraocular pressure (IOP). The increase in IOP is believed to be caused by an increase in the deposition of extracellular matrix proteins, in particular fibronectin, in a region of the eye known as the trabecular meshwork (TM). How fibronectin contributes to the increase in IOP is not well understood. The increased density of fibronectin fibrils is thought to increase IOP by altering the compliance of the trabecular meshwork. Recent studies, however, also suggest that the composition and organization of fibronectin fibrils would affect IOP by changing the cell-matrix signaling events that control the functional properties of the cells in the trabecular meshwork. In this article, we will discuss how changes in the properties of fibronectin and fibronectin fibrils could contribute to the regulation of IOP.

Microfluidic models of physiological or pathological flow shear stress for cell biology, disease modeling and drug development

2019 ◽  
Vol 117 ◽  
pp. 186-199 ◽  
Author(s):  
Huaying Chen ◽  
Zhihang Yu ◽  
Siwei Bai ◽  
Huaxiu Lu ◽  
Dong Xu ◽  
...  
Keyword(s):  
Shear Stress ◽  
Drug Development ◽  
Cell Biology ◽  
Disease Modeling ◽  
Flow Shear ◽  
Flow Shear Stress

scholarly journals Advanced human carotid plaque progression correlates positively with flow shear stress using follow-up scan data: An in vivo MRI multi-patient 3D FSI study

2010 ◽  
Vol 43 (13) ◽  
pp. 2530-2538 ◽  
Author(s):  
Chun Yang ◽  
Gador Canton ◽  
Chun Yuan ◽  
Marina Ferguson ◽  
Thomas S. Hatsukami ◽  
...  
Keyword(s):  
Shear Stress ◽  
Carotid Plaque ◽  
Plaque Progression ◽  
Flow Shear ◽  
Flow Shear Stress ◽  
Scan Data ◽  
Human Carotid

The Influence of Temperature and Humidity on the ABS Contaminations

2014 ◽  
Author(s):  
Fuhao Cui ◽  
Jinhong Hu ◽  
Yue Peng ◽  
Hui Li ◽  
Shengnan Shen ◽  
...  
Keyword(s):  
Shear Stress ◽  
Flow Pattern ◽  
Air Flow ◽  
Disk Drive ◽  
Flying Height ◽  
Flow Shear ◽  
Slip Boundary ◽  
Temperature And Humidity ◽  
Flow Shear Stress ◽  
The Impact

In order to increase the areal recording density of hard disk drive beyond 1 Tb/in2, the flying height has to be reduced to several nanometers. At such a low flying height, particles and lube contaminations, which could lead to a transient vibration and flying height modulation in a hard disk drive, are becoming more and more serious. In this work, it studies the influence of temperature and humidity on the air flow pattern, velocity and shear stress distribution on the air bearing surface (ABS) of slider using a self-developed simulator. It first solves the generalized steady state Reynolds equation with slip boundary conditions. Then it solves the reduced Navier-Stokes (N-S) equation with slip boundary conditions to get the air velocity distribution, i.e., identify the air flow pattern on the ABS. The stagnation lines and areas of air flow are calculated to judge the contamination area. On the other hand, it calculates the air shear stress distribution on the ABS since the air shear stress is the main driving force for the lubricant and particles migration and contaminations. After that, the impact of the temperature and humidity on the air flow pattern is analyzed by applying the Sutherland equation and mixed gas viscosity calculation equation. The simulation results indicate that the impact of temperature and humidity on the air flow pattern is un-conspicuous. However, the peak velocity of the air flow, which contains no vapor, reduces almost 10%, and the peak air flow shear stress increases less than 1.5%, with the increase of operational temperature from 298.15 K to 343.15 K. In addition, the peak velocity of the air flow increasing almost 4%, and the peak air flow shear stress keeps almost same, with the increase of the operational mole fraction of vapor from 5% to 15%.

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