Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes

Abstract

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.

miR-130a and Tgfβ Content in Extracellular Vesicles Derived from the Serum of Subjects at High Cardiovascular Risk Predicts their In-Vivo Angiogenic Potential

“…VEGFR3 is expressed by lymphatic vessels and drives lymphangiogenesis by binding to VEGF-C 40 . The impairment of VEGF-C-induced lymphangiogenesis via the epsin-mediated degradation of VEGFR3 has recently been reported in T2DM 41 . No differences in the number of VEGFR3 + sEV were detected.…”

Metabolic regulation through the endosomal system

“…Consistent with this possibility, conditional knockout of EPN1 and EPN2 in lymphatic endothelial cells prevent VEGF‐C‐induced vascular endothelial growth factor receptor 3 (VEGFR3) from endocytosis and degradation . VEGFR3 is essential for lymphatic vessel growth and lymphangiogenesis, and was found to drop during diabetes . Interestingly, the loss of lymphatic‐specific epsins alleviates insufficient lymphangiogenesis in diabetic mice, indicating a novel approach to treating diabetic complications …”

“…VEGFR3 is essential for lymphatic vessel growth and lymphangiogenesis, and was found to drop during diabetes . Interestingly, the loss of lymphatic‐specific epsins alleviates insufficient lymphangiogenesis in diabetic mice, indicating a novel approach to treating diabetic complications …”

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

“…Lymphatic function was impaired in rats with metabolic syndrome (Zawieja et al, 2012;Gasheva et al, 2019) and in obese mice (Weitman et al, 2013;Blum et al, 2014;García Nores et al, 2016), and defective lymphatics contributed to obesity and metabolism syndrome (Escobedo and Oliver, 2017;Gasheva et al, 2019). Diabetes in mice was associated with impaired lymphangiogenesis and disrupted lymphatic integrity (Scallan et al, 2015;Wu et al, 2018). The lymphatic system has also been implicated in the pathogenesis of atherosclerosis and cardiovascular disease (Aspelund et al, 2016).…”