Journal Article

The Schlemm’s canal is a VEGF-C/VEGFR-3–responsive lymphatic-like vessel

Stanczuk, Lukas, Immonen, Ilkka, Aspelund, Aleksanteri, Tammela, Tuomas, Mäkinen, Taija, Saharinen, Pipsa, Zarkada, Georgia, Francois, Mathias, Antila, Salli, Leppänen, Veli-Matti, Alitalo, Kari, Nurmi, Harri

2014

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Aqueous Humor - physiology / Biomedical research / Care and treatment / Cell adhesion & migration / Cell Movement / Cell Proliferation / Colleges & universities / Cornea - blood supply / Danio rerio / Development and progression / Endothelial Cells - physiology / Endothelium / Glaucoma / Humans / Intraocular Pressure / Laboratory animals / Lymphatic system / Lymphatic Vessels - physiology / Mice / Mice, Inbred C57BL / Microscopy / Objectives / Ophthalmology / Patient outcomes / Risk factors / Rodents / Signal transduction / Smooth muscle / Transcription factors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor C - physiology / Vascular Endothelial Growth Factor Receptor-3 - physiology / Veins & arteries