State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510060, China.
Cell Rep. 2024 Feb 27;43(2):113799. doi: 10.1016/j.celrep.2024.113799. Epub 2024 Feb 16.
Schlemm's canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing SC development and functionality remains limited. Here, we show that vitronectin (VTN) produced by limbal macrophages promotes SC formation and prevents intraocular hypertension by activating integrin αvβ3 signaling. Genetic inactivation of this signaling system inhibited the phosphorylation of AKT and FOXO1 and reduced β-catenin activity and FOXC2 expression, thereby causing impaired Prox1 expression and deteriorated SC morphogenesis. This ultimately led to increased IOP and glaucomatous optic neuropathy. Intriguingly, we found that aged SC displayed downregulated integrin β3 in association with dampened Prox1 expression. Conversely, FOXO1 inhibition rejuvenated the aged SC by inducing Prox1 expression and SC regrowth, highlighting a possible strategy by targeting VTN/integrin αvβ3 signaling to improve SC functionality.
施莱姆氏管（SC）通过排出房水来维持适当的眼内压（IOP），它已成为治疗青光眼的一个有前途的靶点，青光眼是全球第二大致盲的原因。然而，我们对控制 SC 发育和功能的机制的理解仍然有限。在这里，我们表明，由角膜缘巨噬细胞产生的 vitronectin (VTN) 通过激活整合素 αvβ3 信号来促进 SC 的形成并预防眼内高压。这种信号系统的基因失活抑制了 AKT 和 FOXO1 的磷酸化，并降低了 β-catenin 的活性和 FOXC2 的表达，从而导致 Prox1 表达受损和 SC 形态发生恶化。这最终导致眼压升高和青光眼视神经病变。有趣的是，我们发现衰老的 SC 与 Prox1 表达降低相关的整合素β3 下调。相反，FOXO1 的抑制通过诱导 Prox1 表达和 SC 再生使衰老的 SC 恢复活力，这突出了一种通过靶向 VTN/整合素 αvβ3 信号来改善 SC 功能的可能策略。
