Biology subjects

Tseng, Y.-T.

Publications and source records attributed to Tseng, Y.-T..

2 recordsLinked to original sources

bioRxiv2024

TRPV4 overactivation enhances cellular contractility and drives ocular hypertension in TGFβ2 overexpressing eyes

The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-{beta}2 (TGF{beta}2) in the aqueous humor. Effective treatment of POAG requires detailed understanding of interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological and tonometric strategies to establish the role of TGF{beta}2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels, and intraocular pressure (IOP) regulation in a mouse model of TGF{beta}2 -induced OHT. TGF{beta}2 upregulated expression of TRPV4 and PIEZO1 transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 agonists induced contractility of TM-seeded hydrogels whereas pharmacological inhibition suppressed TGF{beta}2-induced hypercontractility and abrogated OHT in eyes overexpressing TGF{beta}2. Trpv4-deficient mice resisted TGF{beta}2-driven increases in IOP, but nocturnal OHT was not additive to TGF{beta}-evoked OHT. Our study establishes the fundamental role of TGF{beta} as a modulator of mechanosensing in nonexcitable cells, identifies the TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT, and offers insights for future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.

physiology↗

bioRxiv2024

Osmosensing in trabecular meshwork cells

Aqueous humor drainage from the anterior eye constitutes a key determinant of intraocular pressure (IOP) under homeostatic and pathological conditions. Swelling of the trabecular meshwork (TM) increases its flow resistance but the mechanisms that sense and transduce osmotic gradients remain poorly understood. We used optical molecular analyses, optical imaging and electrophysiology to investigate TM osmotransduction and its role in calcium and chloride homeostasis. Anisosmotic conditions elicited proportional changes in TM cell volume. Swelling, but not shrinking, evoked increases in intracellular calcium concentration [Ca2+]TM. Hypotonicity-evoked calcium signals were sensitive to HC067047, a selective blocker of TRPV4 channels, whereas the agonist GSK1016790A promoted swelling under isotonic conditions. TRPV4 inhibition partially suppressed hypotonicity-induced volume increases and reduced the magnitude of the swelling-induced membrane current, with a substantial fraction of the swelling-evoked current abrogated by Cl- channel antagonists DIDS and niflumic acid. The volume-sensing transcriptome of primary human TM cells showed expression of TRPV4, TRPM4, AQP1, and TMEMC3B genes. Cl- channel expression was dominated by ANO6 transcripts, auxiliary levels of ANO3, ANO7 and ANO10 and modest expression of LTTRC genes that encode volume-activated anion channels. Thus, TRPV4-mediated cation influx works with Cl- efflux to sense and respond to osmotic stress, potentially contributing to pathological swelling, calcium overload and intracellular signaling that could exacerbate functional disturbances in inflammatory disease and glaucoma.

physiology↗