Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes

J Clin Invest. 2018 Aug 31;128(9):4025-4043. doi: 10.1172/JCI96063. Epub 2018 Aug 13.


Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C-induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C-induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LECs isolated from diabetic LEC-iDKO mice elevated in vitro proliferation, migration, and tube formation in response to VEGF-C over diabetic WT mice. Mechanistically, ROS produced in diabetes induced c-Src-dependent but VEGF-C-independent VEGFR3 phosphorylation, and upregulated epsins through the activation of transcription factor AP-1. Augmented epsins bound to and promoted degradation of newly synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Preclinically, the loss of lymphatic-specific epsins alleviated insufficient lymphangiogenesis and accelerated the resolution of tail edema in diabetic mice. Collectively, our studies indicate that inhibiting expression of epsins in diabetes protects VEGFR3 against degradation and ameliorates diabetes-triggered inhibition of lymphangiogenesis, thereby providing a novel potential therapeutic strategy to treat diabetic complications.

Keywords: Angiogenesis; Diabetes; Lymph; Mouse models; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / deficiency*
  • Adaptor Proteins, Vesicular Transport / genetics
  • Animals
  • CSK Tyrosine-Protein Kinase
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Lymphangiogenesis / physiology*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Proteolysis
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*
  • src-Family Kinases / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Epn2 protein, mouse
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • Vascular Endothelial Growth Factor C
  • epsin
  • vascular endothelial growth factor C, mouse
  • Vascular Endothelial Growth Factor Receptor-3
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human