Diabetes is a chronic and complex metabolic disease. Chronic high glucose exposure produces impaired angiogenesis/lymphangiogenesis during wound healing resulting in skin ulcerations of the lower extremities (leading cause of non-traumatic lower limb amputation) and making diabetes a leading cause of morbidity and mortality. Vascular endothelial growth factor receptors (VEGFR2/3) are critical regulators of angiogenesis and lymphangiogenesis. Importantly, VEGFR2/3 is significantly reduced in the vascular endothelium of diabetic patients. However, the mechanisms responsible for the VEGFR2/3 loss remain poorly understood. Prolonged high glucose exposure reportedly induces ligand-independent degradation of Golgi-localized VEGFR2; however the degradative pathway has not been defined. Intriguingly, we unveil that diabetic conditions elevate autophagosome components, Ulk1 and LC3B and induce VEGFR2/3 targeting to autophagosomes. Given that VEGFR2/3 depletion drives impaired diabetic wound healing, whether autophagosomes mediate degradation of Golgi-localized VEGFR2 is a highly significant and open question. Our latest data show that epsins, endocytic adaptor proteins critical for ligand-induced VEGFR2/3 internalization and degradation in physiologic conditions, are upregulated and interact with Ulk1/LC3B and VEGFR2/3 in autophagosomes in diabetes. Epsin deficiency inhibits diabetes-induced loss of cell surface VEGFR2/3 independent of VEGF. Thus, we hypothesize that epsins promote the degradation of cell surface VEGFR2/3 by targeting VEGFR2/3 to autophagosomes, and autophagic degradation downregulates both new synthesized Golgi-localized and cell surface VEGFR2/3 to effectively decrease VEGFR2/3 levels in diabetic endothelium. Lastly, we hypothesize that disrupting epsins and Ulk1 to protect VEGFR2/3 from diabetic-induced autophagic degradation may offer a new therapeutic strategy to combat retarded diabetic wound healing.
In Aim 1, we will determine mechanisms underlying diabetes-induced degradation of intracellular VEGFR2/3. The proposed studies will identify novel mechanisms by which LC3B and Ulk1 mediate degradation of Golgi-localized VEGFR2/3 in the diabetic endothelium.
In Aim 2, we will determine mechanisms of diabetes-induced cell surface VEGFR2/3 autophagic degradation. These studies will provide novel information on how epsins and Ulk1/LC3B cooperatively regulate ligand-independent cell surface VEGFR2/3 degradation.
In Aim 3, we will examine the therapeutic potential of epsins and Ulk1 null animals in diabetic angiogenesis using in vitro angiogenesis assays and in vivo diabetic wound healing and Matrigel plug assays in our novel db/db and Akita diabetic mouse models with combinatorial conditional depletion of endothelial epsins and Ulk1. These studies will shed light upon the beneficial effects of epsins and Ulk1 loss in diabetes, and test the combinatory therapeutic potential of epsin and Ulk1 inhibition in the treatment of defective diabetic peripheral angiogenesis.

Public Health Relevance

Diabetes is a chronic and complex metabolic disease characterized as a state of chronic hyperglycemia; the plethora of secondary micro- and macrovascular dysfunctions that stem from the endothelial cytotoxic effects of chronic high glucose exposure, including impaired angiogenesis and lymphangiogenesis during wound healing resulting in skin ulcerations of the lower extremities (leading cause of non-traumatic lower limb amputation), make diabetes a leading cause of morbidity and mortality. In current application, we will define a novel degradative pathway leading to the loss of VEGF receptors in diabetic endothelium, contributing to defective angiogenesis/lymphangiogenesis during impaired wound healing in diabetic patients the findings will identify potential new targets and provide useful information on developing critical reagents to advance the therapeutic intervention of diabetic peripheral vascular complications.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Gao, Yunling
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Children's Hospital Boston
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Dong, Yunzhou; Fernandes, Conrad; Liu, Yanjun et al. (2017) Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis. Diab Vasc Dis Res 14:14-23
Li, Manna; Qian, Ming; Xu, Jian (2017) Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance. Front Cardiovasc Med 4:51
Dong, Yunzhou; Cai, Xue; Wu, Yong et al. (2017) Insights from Genetic Model Systems of Retinal Degeneration: Role of Epsins in Retinal Angiogenesis and VEGFR2 Signaling. J Nat Sci 3:
Song, Kai; Wu, Hao; Rahman, H N Ashiqur et al. (2017) Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis. Cell Mol Life Sci 74:393-398
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Rahman, H N Ashiqur; Wu, Hao; Dong, Yunzhou et al. (2016) Selective Targeting of a Novel Epsin-VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis. Circ Res 118:957-969
Cha, Boksik; Geng, Xin; Mahamud, Md Riaj et al. (2016) Mechanotransduction activates canonical Wnt/?-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev 30:1454-69
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2015) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 125:4349-64
Chang, Baojun; Tessneer, Kandice L; McManus, John et al. (2015) Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development. Nat Commun 6:6380

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