Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes

Lymphangiogenesis occurs in adult tissues of chronic complex diseases, including diabetes. Whether lymphangiogenesis is altered owing to diabetic complication remains unknown. VEGF-C/VEGFR-3 signaling axis fuels the growth of lymphatic vessels. How VEGF-C/VEGFR3 signaling is regulated under pathological conditions, such as diabetes, however, is poorly understood. Here, we report that mice with inducible lymphatic endothelial cell-specific deficiency of epsins 1 and 2 (LEC-iDKO) display enhanced lymphangiogenesis compared to wild type (WT) in diabetic condition. A profound increase in VEGF-C-induced lymphatic vessel growth is exhibited in corneas and subcutaneous Matrigel implanted in diabetic LEC-iDKO mice compared to diabetic WT mice. Conversely, lymphatic endothelial cells isolated from diabetic WT mice show marked impairment in proliferation, migration, and tube formation in response to VEGF-C relative to those from diabetic LEC-iDKO in vitro . Mechanistically, reactive oxygen species (ROS) generated from hyperglycemia induces c-Src-dependent VEGFR3 phosphorylation independent of VEGF-C, which parallels c-Src-dependent epsin upregulation through the transcription factor AP-1. Heightened epsin expression induced by ROS facilitates epsin binding to VEGFR3 within Golgi compartment, promoting degradation of newly synthesized VEGFR3, and progressively reducing availability of VEGFR3 at the cell surface. Consequentially, lymphatic-specific epsin loss strengthens insufficient lymphangiogenesis and improves the resolution of tail edema in diabetic mice. Collectively, our data indicate that inhibiting epsin expression protects VEGFR3 against degradation and ameliorates diabetes-triggered downregulation of lymphangiogenesis, providing a plausible original therapeutic strategy to treat diabetic complication. Disclosure H. Chen: None.