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Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity
Dae-Young Park, … , Young-Kwon Hong, Gou Young Koh
Dae-Young Park, … , Young-Kwon Hong, Gou Young Koh
Published July 25, 2014
Citation Information: J Clin Invest. 2014;124(9):3960-3974. https://doi.org/10.1172/JCI75392.
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Research Article Article has an altmetric score of 18

Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity

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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 Park, Junyeop Lee, Intae Park, Dongwon Choi, Sunju Lee, Sukhyun Song, Yoonha Hwang, Ki Yong Hong, Yoshikazu Nakaoka, Taija Makinen, Pilhan Kim, Kari Alitalo, Young-Kwon Hong, Gou Young Koh

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Figure 4

VEGF-C/VEGFR3 system plays a crucial role in the early development of SC.

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VEGF-C/VEGFR3 system plays a crucial role in the early development of SC...
(A–C) β-Gal staining of corneas in VEGF-C–β-gal knockin reporter mice (Vegfc+/LacZ) at P1 and 1 month. Robust VEGF-C expression in superficial layer of cornea (white arrowhead) and iris (black arrowhead) at P1 is shown, while rarer VEGF-C expression in TM (black arrow) and iris (black arrowhead) at 1 month is shown. (D) Prox1 and CD31 staining of SC ECs in Vegfc+/LacZ and Vegfc+/+ mice during postnatal development. Arrowheads indicate buddings of SC ECs. Arrows indicate holes in SC, which denote defects of tubular fusion. (E and F) Comparisons of relative area and Prox1 expression of SC. The area and Prox1 expression of Vegfc+/+ at 1 month was set as 100%, respectively. n = 4, each group. *P < 0.05 versus Vegfc+/+. (G and H) Mice were i.p. given sVEGFR3 (25 mg/kg) daily from P1 to P6 and designated as control Fc and sVEGFR3; corneas were harvested at P7. (G) Image showing CD31+ SC ECs. (H) Comparison of relative SC area. The quantification of control Fc group was normalized to 100%, from which the quantifications of other groups were calculated. n = 4, each group. *P < 0.05 versus control Fc. Scale bars: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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