Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes
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
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
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Research Article Angiogenesis Vascular biology

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.

Authors

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

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Figure 7

Epsin deficiency improves the resolution of tail edema by preventing the degradation of VEGFR3 in diabetic mice.

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Epsin deficiency improves the resolution of tail edema by preventing the...
(A) Representative images of postoperative tail edema of WT (n = 8), LEC-iDKO (n = 8), WT/STZ/HFD (n = 8), and DKO/STZ/HFD (n = 8) mice at postoperative day 16. (B) Quantification of tail volume distal to the incision of postoperative tail edema of WT (n = 8), LEC-iDKO (n = 8), WT/STZ/HFD (n = 8), and DKO/STZ/HFD (n = 8) mice at postoperative days 1, 7, 10, 14, 18, 21, 24, and 28. (C and D) Representative immunofluorescence staining of tail sections of WT, LEC-iDKO, WT/STZ/HFD, and LEC-iDKO/STZ/HFD mice at postoperative day 29 with antibodies against LYVE-1 (green) and VEGFR3 (red). The quantification of immunofluorescence staining of tail sections of C is shown in D (n = 5). (E and F) Representative fluorescence microlymphangiography of FITC-dextran injection into tails of WT (n = 5), LEC-iDKO (n = 5), WT/STZ/HFD (n = 5), and LEC-iDKO/STZ/HFD (n = 5) mice at postoperative day 30, and analyzed by 3 independent experiments. Two red dashed lines indicate the incision of tails. Black arrow under the image marks the direction of lymphatic transport. Four cyan arrows indicate the FITC-dextran labeling fluorescence intensity after crossing the incision to other side of the tail at 0, 5, 10, and 15 minutes, respectively. Quantification of FITC-dextran labeling intensity posed after crossing the incision in F. Data are mean ± SEM. *P < 0.05, by 2-way ANOVA followed by Tukey’s post hoc test. Scale bars: 8 mm (A and E); 50 μm (C).