Abstract 607: Modulating VEGFR3 Signaling by Epsins Regulates Lymphatic Dysfuntion in Diabetes

Abstract

Background: Impaired lymphatic function in diabetes is a major cause of lymphedema and immune suppression. VEGFR3 signaling is a master regulator of lymphatic development; however, whether alteration of VEGFR3 signaling regulates lymphatic function in diabetes is unknown. We uncovered that loss of epsins in lymphatic endothelial cells (LECs) increases VEGFR3 signaling by hindering VEGFR3 downregulation (Science Signaling, 2014). The goals for the present study were (1) to determine if hyperglycemia inhibits VEGFR3 signaling and impairs lymphangiogenesis, (2) identify critical molecular pathways that drive the upregulation of epsin, leading to enhanced degradation of VEGFR3 in diabetes, (3) to ascertain if elevated VEGFR3 signaling caused by epsin loss is crucial for restoring impaired lymphatic circulation in diabetes. Methods and Results: Using innovative near-infrared imaging and tail lymphedema models, we showed that epsin loss accelerates recovery from diabetic secondary lymphedema. We also found that hyperglycemia-induced oxidative stress attenuates VEGFR3 signaling, delays diabetic secondary lymphedema resolution, however, elevates epsin expression in LECs. Mechanistically, using ChIP and luciferase reporter analyses, we discovered that hyperglycemia driven oxidative stress-induced Src activation stimulates AP1 activity, which in turn binds epsin promoter and upregulates epsin transcription. Consequently, heightened epsin expression in primary LECs isolated from diabetic mice suppresses VEGFR3 signaling and prohibits lymphangiogenesis by facilitating VEGFR3 downregulation. Conversely, epsin deficiency rescues high-glucose-induced VEGFR3 loss, amends defective lymphangiogenesis, and ameliorates diabetic secondary lymphedema. Conclusions: Epsin depletion promotes diabetic secondary lymphedema resolution by protecting VEGFR3 from oxidative stress-induced degradation, highlighting the therapeutic potential for targeted inhibition of epsins in the lymphatic endothelium as a treatment for lymphatic dysfunction in diabetes.