Schlemm’s canal: lymphatic origins revealed
Schlemm’s canal (SC) is a specialized structure that functions to drain aqueous humor from the eye and return it to the systemic circulation. SC dysfunction inhibits the outflow of aqueous humor, resulting in increased intraocular pressure (IOP), which is a risk factor for ocular diseases such as glaucoma. Two research groups, one led by Kari Alitalo at the University of Helsinki and one led by Gou Young Koh at the Korea Advanced Institute of Science and Technology, reveal that lymphangiogenic regulators are critical for the proper development and function of SC. Both groups found that SC expresses lymphatic endothelial markers, including the transcription factor PROX1 and the RTK VEGFR3. Koh and colleagues showed that developmental and pathological changes in aqueous humor outflow altered the fate of SC endothelial cells, with the lymphatic marker PROX1 becoming undetectable under pathological conditions. Alitalo and colleagues demonstrated that delivery of the lymphatic growth factor VEGF-C into the adult eye promotes growth, sprouting, and proliferation of SC endothelial cells and reduces IOP. In the accompanying commentary, Natalie Karpinich and Kathleen Caron of the University of North Carolina indicate that the lymphatic characteristics of SC provide potential therapeutic and diagnostic targets for treating IOP-associated pathologies. The accompanying image from the Alitalo group shows a 90° y-axis projection of the aqueous humor drainage route in the adult murine eye. The episcleral (ES) blood vessels and the aqueous vein (AV) are positive for the blood vessel marker PECAM-1 (green), while ES lymphatic vessels are positive for lymphatic markers PROX1 (red) and VEGF-3 (blue). SC is positive for all three markers.
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Abstract
In glaucoma, aqueous outflow into the Schlemm’s canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.
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Aleksanteri Aspelund, Tuomas Tammela, Salli Antila, Harri Nurmi, Veli-Matti Leppänen, Georgia Zarkada, Lukas Stanczuk, Mathias Francois, Taija Mäkinen, Pipsa Saharinen, Ilkka Immonen, Kari Alitalo
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
Abstract
Schlemm’s canal (SC) is a unique vascular structure that functions to maintain fluid homeostasis by draining aqueous humor from the eye into the systemic circulation. The endothelium lining the inner wall of SC has both blood and lymphatic vascular characteristics, thus prompting exploration of the development and regulation of this unique channel. In this issue of the
Authors
Natalie O. Karpinich, Kathleen M. Caron
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