Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm’s canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.

中文翻译：

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血管生成素/Tie2 信号传导受损会损害施累姆氏管完整性并诱发青光眼


原发性开角型青光眼 (POAG) 通常是由眼内压 (IOP) 升高引起，眼压升高是由于房水流出 (AHO) 阻力增加所致。房水流经施累姆氏管（SC）（一种环绕角膜的淋巴样血管），并流经睫状肌细胞的细胞间隙。然而，AHO 耐药性增加的机制尚不清楚。在这里，我们证明血管生成素 (Angpt) 和 Angpt 受体 Tie2 之间的信号传导对于 SC 形成至关重要，对于成年期间维持 SC 完整性也是不可或缺的。成年小鼠中Angpt1 / Angpt2或Tie2的缺失会严重损害 SC 完整性和转胞吞作用，导致 IOP 升高、视网膜神经元损伤和视网膜神经节细胞功能受损，这些都是人类 POAG 的标志。我们发现 SC 完整性是通过 Angpt-Tie2 信号传导、AHO 和 Prox1 活动的互连和协调功能来维持的。 SC 的这些功能在衰老过程中会减弱，导致完整性和转胞吞作用受损。有趣的是，使用 Tie2 激动性抗体重新激活 Tie2 可挽救Angpt1 / Angpt2缺陷小鼠的 POAG 表型，并使老年小鼠的 SC 恢复活力。这些结果表明 Angpt-Tie2 系统对于 SC 完整性至关重要。该系统的损伤是 POAG 相关发病机制的基础，支持 Tie2 激动剂可能成为青光眼治疗选择的可能性。