Kizhatil Krishnakumar, Clark Graham M, Sunderland Daniel K, Bhandari Aakriti, Horbal Logan J, Balasubramanian Revathi, John Simon W M
Department of Ophthalmology and Visual Sciences, The Ohio State Medical Center, Columbus, Ohio, 43210, USA.
The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
Nat Commun. 2025 Jan 2;16(1):51. doi: 10.1038/s41467-024-55232-8.
Schlemm's canal endothelial cells (SECs) serve as the final barrier to aqueous humor (AQH) drainage from the eye. SECs adjust permeability to AQH outflow to modulate intraocular pressure (IOP). The broad identification of IOP-related genes implicates SECs in glaucoma. However, the molecular mechanisms by which SECs sense and respond to pressure changes to regulate fluid permeability and IOP remain largely undefined. We hypothesize that mechano-responsive phosphorylation of the cell adhesion molecule VE-CADHERIN (CDH5) in SECs, by FYN and possibly other SRC family kinases, regulates adherens junction (AJ) permeability to AQH in response to IOP. On experimentally raising IOP in mouse eyes, AJ permeability, CDH5 phosphorylation, and FYN activation at the AJ all increase. FYN null mutant mice display disrupted IOP regulation and reduced AQH outflow. These findings demonstrate an important role of mechanotransducive signaling within SECs in maintaining IOP homeostasis and implicate FYN as a potential target for developing IOP-lowering treatments.
施莱姆管内皮细胞（SECs）是眼内房水（AQH）引流的最后一道屏障。SECs通过调节对AQH流出的通透性来调控眼压（IOP）。与IOP相关基因的广泛鉴定表明SECs与青光眼有关。然而，SECs感知并响应压力变化以调节液体通透性和IOP的分子机制在很大程度上仍不清楚。我们推测，在SECs中，细胞黏附分子血管内皮钙黏蛋白（CDH5）通过FYN以及可能的其他SRC家族激酶进行机械响应性磷酸化，从而响应IOP调节黏附连接（AJ）对AQH的通透性。在实验性升高小鼠眼压时，AJ通透性、CDH5磷酸化以及AJ处的FYN激活均增加。FYN基因敲除突变小鼠表现出眼压调节紊乱和AQH流出减少。这些发现证明了SECs内机械转导信号在维持眼压稳态中的重要作用，并表明FYN是开发降低眼压治疗方法的潜在靶点。
