Abstract 13426: Suppression of Epsin Expression Rescues Diabetes Triggered Impaired Lymphatic Function by Limiting VEGFR3 Degradation
Rationale: Impaired lymphatic circulation causes lymphedema and contributes to pathological conditions, such as diabetes. VEGF-C/VEGFR3 signaling is a crucial regulator of lymphatic development; however, whether manipulation in signaling improves lymphatic circulation under pathological conditions is unclear.
Objective: We recently uncovered that loss of epsins in lymphatic endothelial cells (LECs) caused heightened VEGFR3 signaling and delayed lymphatic formation during development. Herein, we investigated whether elevated VEGFR3 signaling caused by epsin loss is critical for pathological lymphatic circulation in adult mice.
Methods and Results: Using innovative near-infrared lymphatic imaging, and tail lymphedema models, we demonstrated that epsin loss accelerated recovery from diabetic secondary lymphedema. High-glucose-induced oxidative stress results in reduced VEGFR3 signaling, impaired lymphangiogenesis and delayed recovery from diabetic secondary lymphedema. The dual luciferase reporter assay system and ChIP assay showed in STZ-induced diabetic mice drove Src- and AP-1- mediated upregulation of epsin expression. Epsin deletion in primary LECs caused heightened VEGFR3 signaling and promoted in vitro lymphangiogenesis by preventing VEGFR3 downregulation. Mechanistically, we showed that by protecting cell surface VEGFR3 from degradation, lack of epsin rescued high-glucose-induced VEGFR3 loss, defective lymphangiogenesis in vitro, and ameliorated STZ-induced diabetic secondary lymphedema in vivo.
Conclusions: Epsins essentially regulate lymphatic circulation through the modulation of VEGFR3 signaling. In STZ- induced diabetic mice, Src induces epsin expression via transcription factor AP-1. Epsin depletion ameliorated diabetic secondary lymphedema under hyperglycemic condition by protecting VEGFR3 from oxidative stress-induced degradation. Our findings highlight the therapeutic potential for targeted inhibition of epsins within the lymphatic endothelium as a treatment for secondary lymphedema caused by uncontrolled diabetes.
Key Words: Epsin, VEGFR3, Lymphatics, Secondary Lymphedema, Diabetes
Author Disclosures: H. Chen: None.
- © 2016 by American Heart Association, Inc.