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

Rudzitis, C. N.; Lakk, M.; Singh, A.; Redmon, S. N.; Kirdajova, D.; Tseng, Y.-T.; deIeso, M. L.; Stamer, D.; Herberg, S.; Krizaj, D.

doi:10.1101/2024.11.05.622187

bioRxiv · 10.1101/2024.11.05.622187

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

Rudzitis, C. N.·Lakk, M.·Singh, A.·Redmon, S. N.·Kirdajova, D.·Tseng, Y.-T.·deIeso, M. L.·Stamer, D.·Herberg, S.·Krizaj, D.

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Abstract

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.

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Rudzitis, C. N., Lakk, M., Singh, A., Redmon, S. N., Kirdajova, D., Tseng, Y.-T., deIeso, M. L., Stamer, D., Herberg, S., Krizaj, D.. 2024-11-08. TRPV4 overactivation enhances cellular contractility and drives ocular hypertension in TGFβ2 overexpressing eyes. https://doi.org/10.1101/2024.11.05.622187

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