SIGNIFICANCE: Previous evidence showed that transient receptor potential vanilloid 4 (TRPV4) inhibition was protective of retinal ganglion cell (RGC) loss after chronic intraocular pressure (IOP) elevation in young animals. However, the role of TRPV4 in mechanosensing IOP changes in the aging eye is not well understood. PURPOSE: This study compared the recovery of retinal function and structure after acute IOP elevation in 3- and 12-month-old mouse eyes with and without TRPV4 inhibition. METHODS: We examined retinal TRPV4 expression in 2-month-old rodent eyes using immunohistochemistry and transcript analysis of isolated macroglia and RGCs. To modulate TRPV4, mice were treated daily with either vehicle or a TRPV4 antagonist (HC-067047 10 mg/kg) delivered intraperitoneally for 7 days before and 7 days after IOP elevation (50 mmHg for 30 minutes). Retinal function and structure were assessed using dark-adapted full-field electroretinography and optical coherence tomography, respectively. RESULTS: We showed that Müller cells strongly expressed TRPV4. Seven days after IOP elevation, RGC functional recovery was significantly poorer in older mice treated with TRPV4 antagonist compared with age-matched vehicle controls (-54 ± 7% vs. -24 ± 10%, p=0.046) and their younger TRPV4 antagonist-treated counterparts (-5 ± 5%, p<
0.001). CONCLUSIONS: This study showed that there was an age-related deficit in RGC functional recovery from IOP elevation with TRPV4 inhibition.