Macrophage-induced integrin signaling promotes Schlemm's canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy.

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. [Display omitted] • Macrophage-derived VTN signal through integrin αvβ3 regulates SC morphogenesis and IOP • VTN/integrin αvβ3 signal promotes Prox1 expression and lymphatic specification of SC • Endothelial integrin αvβ3 activates lymphangiogenic AKT/FOXO1/β-catenin/FOXC2 pathway • FOXO1 inhibition rejuvenates aged SC by inducing SC regrowth Gu et al. establish a homeostatic mechanism governing Schlemm's canal (SC) morphogenesis. They show that macrophage crosstalk with endothelial cells lining the developing SC induces vitronectin/integrin αvβ3 signaling. The establishment of this interaction activates a major lymphangiogenic signaling pathway, thereby promoting SC specification and formation to maintain proper intraocular pressure. [ABSTRACT FROM AUTHOR]