Lymphatic regulator PROX1 determines Schlemm’s canal integrity andidentity

摘要

Schlemm’s canal (SC) is a specialized vascular structure in the eye that functionsto drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunctionof 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, whichoriginates from blood vessels during the postnatal period, acquires lymphatic identitythrough upregulation of prospero homeobox protein 1 (PROX1), the master regulator oflymphatic development. SC expressed lymphatic valve markers FOXC2 and integrinα_(9) and exhibited continuous vascular endothelial–cadherin(VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SCnotably lacked luminal valves and expression of the lymphatic endothelial cell markerspodoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using anocular puncture model, we determined that reduced AHO altered the fate of SC both duringdevelopment and under pathologic conditions; however, alteration of VEGF-C/VEGFR3signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expressionlevels linearly correlated with SC functionality. For example, PROX1 expression wasreduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively,our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity andidentity.