Pathological angiogenesis is a key process that drives vascular remodeling in numerous cardiovascular and metabolic diseases including diabetic retinopathy, age-related macular degeneration (AMD) and cancer. However, owing to scarcity of proper molecular targets, it is widely recognized that hindering pathological angiogenesis to mitigate these deleterious disease conditions remains daunting. Our long-term goal is to uncover original molecular mechanisms and identify fresh molecules that prevent pathological angiogenesis in hopes of offering potential new therapeutic approaches. In our last funding cycle, we examined the role of endothelial epsins and Dab2 in reciprocally regulating VEGF signaling and created mice with either inducible endothelial-specific epsins 1 and 2 deficiency (EC-iDKO) or endothelial-specific Dab2 deficiency (EC- Dab2iKO). We showed that epsins and Dab2 interact with VEGFR2 via a mutually exclusive mechanism. Interestingly, mice lacking endothelial epsins and Dab2 (EC-iTKO) rescue heightened angiogenesis caused by epsins depletion, or attenuated angiogenesis produced by Dab2 loss, suggesting that epsins and Dab2 antagonizing each other to modulate VEGF-mediated angiogenesis in vivo. Given that VEGF signaling plays a central role in normal, as well as pathological angiogenesis, how epsin and Dab2 are differentially recruited to mediate VEGFR2 internalization and modulate VEGF signaling is a highly significant and open question. In searching for upstream signals that preferentially trigger either epsin or Dab2 binding to VEGFR2, our latest study revealed that Sphigosine 1 Phosphate (S1P) stimulation facilitates epsins but hinders Dab2 binding to VEGFR2, leading to VEGF-induced VEGFR2 degradation. How S1P selectively allows the recruitment of epsins to VEGFR2 is poorly understood. Further, we discover that miRNA (miR-19) directly binds epsins' 3'UTR and represses epsins' expression. Whether miR-19 potentiates VEGF signaling by inhibiting epsins' expression is entirely unclear. Given crucial roles epsins play in regulating angiogenesis, uncovering molecule mechanisms and genetic modifiers that control epsins' activity and govern epsin expression may offer new therapeutic approaches in pathological angiogenesis. To this end, we hypothesize that S1P induced Src activation phosphorylates VEGFR2, enabling VEGFR2:Cbl association and VEGFR2 ubiquitination, and enforcing epsin:VEGFR2 binding and VEGFR2 downregulation. We further hypothesize that epigenetic regulation including miR-19 that directly suppresses epsins' expression, causing heightened VEGF signaling. We will utilize multifactorial approaches to investigate molecular mechanisms responsible for regulating epsin's activity and expression. Lastly, we will determine therapeutic potential of enhancing epsin or S1P function in pathological angiogenesis. If fruitful, our findings will advance our understanding of novel pathways and targets that modulate VEGF signaling, offering a new class of therapeutic strategies, and inaugurating a paradigm shift in research of pathological angiogenesis to fight devastating diseases including AMD, cancer and diabetes.

Public Health Relevance

Pathological angiogenesis plays a leading role in the pathogenesis of diabetic retinopathy, which is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. Pathological angiogenesis also ensures tumor development, progression, and spreading to other parts of body, which is the most common cause of death in the United States. In current application, we will define how prominent anti-angiogenic signaling proteins, epsin and S1Pr1, synergistically control the development of pathological angiogenesis by regulating VEGF signaling. The findings will provide useful information on developing key reagents to advance the precision targeting strategy for therapeutic intervention of pathological angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL093242-10
Application #
9615107
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gao, Yunling
Project Start
2009-07-17
Project End
2022-06-30
Budget Start
2018-07-15
Budget End
2019-06-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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; Fu, Jianxin; Song, Jianhua et al. (2017) Loss of mucin-type O-glycans impairs the integrity of the glomerular filtration barrier in the mouse kidney. J Biol Chem 292:16491-16497
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
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
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
Song, Kai; Herzog, Brett H; Fu, Jianxin et al. (2015) Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice. J Biol Chem 290:20159-66
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
Liu, Xiaolei; Pasula, Satish; Song, Hoogeun et al. (2014) Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal 7:ra97

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