title: Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity.
abstract: Schlemm's canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin α9 and exhibited continuous vascular endothelial-cadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity.
authors: Dae-Young
authors: DY
authors: Park
authors: Junyeop
authors: J
authors: Lee
authors: Intae
authors: I
authors: Park
authors: Dongwon
authors: D
authors: Choi
authors: Sunju
authors: S
authors: Lee
authors: Sukhyun
authors: S
authors: Song
authors: Yoonha
authors: Y
authors: Hwang
authors: Ki Yong
authors: KY
authors: Hong
authors: Yoshikazu
authors: Y
authors: Nakaoka
authors: Taija
authors: T
authors: Makinen
authors: Pilhan
authors: P
authors: Kim
authors: Kari
authors: K
authors: Alitalo
authors: Young-Kwon
authors: YK
authors: Hong
authors: Gou Young
authors: GY
authors: Koh
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001082:Aqueous Humor / Q000502:physiology*; D003315:Cornea / Q000098:blood supply*; D042783:Endothelial Cells / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000502:physiology*; D007429:Intraocular Pressure; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D000199:Actins; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; C544013:alpha-smooth muscle actin, mouse; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3