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.
Hao Wu, H.N. Ashiqur Rahman, Yunzhou Dong, Xiaolei Liu, Yang Lee, Aiyun Wen, Kim H.T. To, Li Xiao, Amy E. Birsner, Lauren Bazinet, Scott Wong, Kai Song, Megan L. Brophy, M. Riaj Mahamud, Baojun Chang, Xiaofeng Cai, Satish Pasula, Sukyoung Kwak, Wenxia Yang, Joyce Bischoff, Jian Xu, Diane R. Bielenberg, J. Brandon Dixon, Robert J. D’Amato, R. Sathish Srinivasan, Hong Chen
ROS-induced phosphorylation of VEGFR3 associated with epsins in the Golgi compartment under diabetic conditions.