title: The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel.
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.
authors: Aleksanteri
authors: A
authors: Aspelund
authors: Tuomas
authors: T
authors: Tammela
authors: Salli
authors: S
authors: Antila
authors: Harri
authors: H
authors: Nurmi
authors: Veli-Matti
authors: VM
authors: Leppänen
authors: Georgia
authors: G
authors: Zarkada
authors: Lukas
authors: L
authors: Stanczuk
authors: Mathias
authors: M
authors: Francois
authors: Taija
authors: T
authors: Mäkinen
authors: Pipsa
authors: P
authors: Saharinen
authors: Ilkka
authors: I
authors: Immonen
authors: Kari
authors: K
authors: Alitalo
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D003315:Cornea / Q000098:blood supply*; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D007429:Intraocular Pressure; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3