Prox1 serves as a biosensor reflecting the integrity and lymphatic identity of schlemm's canal

Abstract

Schlemm’s canal (SC) in the eye is a specialized vascular structure for draining out aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been suspected to be responsible for increased aqueous humor outflow (AHO) resistance, leading to elevated ocular pressure which is an underlying factor for glaucoma in humans. Here SC, which originates from blood vessels during postnatal period, acquires lymphatic identity by upregulating Prox1, the master regulator of lymphatic development. SC expresses Foxc2 and integrin $\alpha$9 and possesses continuous VE-cadherin junctions and basement membrane, resembling collecting lymphatics, but notably lacking luminal valves and expressions of podoplanin and LYVE-1. I evaluated the regulatory mechanisms that alter the fate of SC during both development and pathologic conditions, and identified AHO and Angiopoietin/Tie2 signaling, but not VEGF-C/VEGFR3 signaling, as the main modulator of SC integrity and identity. Intriguingly, the Prox1 expression was linearly correlated to the functionality of SC, where weak or no expressions of Prox1 were observed during pathogenesis and in deteriorated SC compared to normal conditions. Collectively, Prox1 is an accurate and reliable biosensor of SC integrity and identity.