Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity

Blood. 2013 May 16;121(20):4242-9. doi: 10.1182/blood-2012-08-453043. Epub 2013 Mar 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cornea* / drug effects
  • Cornea* / metabolism
  • Cornea* / physiology
  • Corneal Diseases / pathology
  • Corneal Diseases / therapy
  • Corneal Transplantation / methods
  • Graft Survival / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Lymphangiogenesis / drug effects
  • Lymphangiogenesis / genetics*
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Isoforms
  • Solubility
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / pharmacology
  • Vascular Endothelial Growth Factor Receptor-3 / physiology*

Substances

  • Protein Isoforms
  • Vascular Endothelial Growth Factor Receptor-3