Abstract
Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.
Highlights
Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye
Heterozygous loss of function variants in TEK or its primary ligand ANGPT1 have been linked to PCG in children[13,14,15], and ANGPT1 and ANGPT2 have been associated with primary open-angle glaucoma (POAG) in adults[16,17]
We show that deletion of Angpt[1] or Svep[1] from the neural crest tissues giving rise to the TM leads to major defects in the adjacent SC, ocular hypertension and phenotypes similar to PCG
Summary
Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Current therapy is supportive and focused on the reduction of intraocular pressure (IOP), a primary risk factor for glaucoma progression. Patients with high-pressure glaucoma, including primary congenital glaucoma (PCG), a severe, early onset form of the disease, exhibit defects in the conventional pathway, which lead to decreased aqueous humor outflow and elevated IOP6–8. Heterozygous loss of function variants in TEK or its primary ligand ANGPT1 have been linked to PCG in children[13,14,15], and ANGPT1 and ANGPT2 have been associated with primary open-angle glaucoma (POAG) in adults[16,17]. ANGPT1-TEK signaling is required for SC development in mice[13,14,18], suggesting a potential mechanism for IOP elevation
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