title: Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity.
abstract: Corneal transparency is a prerequisite for optimal vision and in turn relies on an absence of blood and lymphatic vessels, which is remarkable given the cornea's proximity to vascularized tissues. Membrane-bound vascular endothelial growth factor receptor 3 (VEGFR-3), with its cognate ligand vascular endothelial growth factor C (VEGF-C), is a major mediator of lymphangiogenesis. Here, we demonstrate that the cornea expresses a novel truncated isoform of this molecule, soluble VEGFR-3 (sVEGFR-3), which is critical for corneal alymphaticity, by sequestering VEGF-C. sVEGFR-3 binds and sequesters VEGF-C, thereby blocking signaling through VEGFR-3 and suppressing lymphangiogenesis induced by VEGF-C. sVEGFR-3 knockdown leads to lymphangiogenesis and hemangiogenesis in the mouse cornea, while overexpression of sVEGFR-3 inhibits lymphangiogenesis and hemangiogenesis in a murine suture injury model. Pax6(+/-) mice spontaneously develop corneal and lymphatic vessels and are deficient in sVEGFR-3. sVEGFR-3 suppresses hemangiogenesis by blocking VEGF-C-induced phosphorylation of VEGFR-2. Overexpression of sVEGFR-3 leads to a 5-fold increase in corneal transplant survival in mouse models. sVEGFR-3 holds promise as a molecule to control and regress lymphatic-vessel-based dysfunction. Therefore, sVEGFR-3 has the potential to protect the injured cornea from opacification secondary to infection, inflammation, or transplant rejection.
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA. nirbhais@gmail.com
authors.forename: Nirbhai
authors.initials: N
authors.lastname: Singh
authors.forename: Michelle
authors.initials: M
authors.lastname: Tiem
authors.forename: Ryan
authors.initials: R
authors.lastname: Watkins
authors.forename: Yang Kyung
authors.initials: YK
authors.lastname: Cho
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Olsen
authors.forename: Hironori
authors.initials: H
authors.lastname: Uehara
authors.forename: Christina
authors.initials: C
authors.lastname: Mamalis
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Zackery
authors.initials: Z
authors.lastname: Oakey
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003316:Corneal Diseases / Q000473:pathology / Q000628:therapy; D016039:Corneal Transplantation / Q000379:methods; D006085:Graft Survival / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020033:Protein Isoforms; D012995:Solubility; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D040321:Vascular Endothelial Growth Factor Receptor-3