Angiogenesis is required for embryogenesis, tumor formation, and wound healing. Signaling by binding of vascular endothelial growth factor (VEGF) to its receptor VEGFR-2 is a major control point for angiogenesis. The magnitude of this signaling pathway is intimately associated with the abundance of VEGFR-2 at the cell surface. Although VEGF-induced endocytosis and degradation control the cell-surface level of VEGFR-2, very little is known about the machinery that governs VEGFR-2 endocytosis and degradation. Epsin is an endocytic adaptor protein that mediates endocytosis of activated receptors. We have generated mutant mice that lack epsin 1 and 2 globally or selectively in endothelial cells. These mutant mice exhibited similar embryonic lethality due to abnormal vascular development typified by increased vessel density and disorganized architecture. VEGFR-2 expression was elevated, reflecting enhanced VEGF function. We hypothesize that epsin-dependent regulation of VEGFR-2 endocytosis and degradation is crucial for VEGF-mediated vascular development and angiogenesis. To test this hypothesis, we will utilize endothelial cell-specific epsin double knockout mice to determine the functions of epsins in regulating angiogenic sprouting, endothelial cell proliferation, and endothelial cell survival. We will engineer tamoxifen inducible endothelial cell-specific epsin double knockout mice to probe the role of epsins in postnatal angiogenesis under physiological and pathological conditions. The in vivo studies will be complemented by in vitro assays of endothelial cell migration, proliferation, tube formation, vessel sprouting, and VEGF-dependent signaling. We will also use biochemical and fluorescent imaging techniques to investigate the interaction of epsins and VEGFR-2 and the role of epsins in VEGF-induced VEGFR-2 endocytosis and degradation. The information gained will help us determine molecular mechanisms by which epsin-mediated endocytosis regulates VEGF signaling and controls vascular development and angiogenesis. These studies should contribute to the application of endocytic components to new therapeutic strategies for cardiovascular diseases and cancer.
New blood vessel formation is critical for both embryogenesis and reparative/ adaptive responses. We will study the role of a novel signaling molecule epsin in the formation of new blood vessels. Our work may lead to better treatments for heart disease that involves new blood vessel formation.
|Dong, Jerry; Saunders, Debra; Silasi-Mansat, Robert et al. (2018) Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis. J Neurooncol 138:17-27|
|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; Wu, Hao; Dong, Jerry et al. (2017) Mimetic peptide of ubiquitin-interacting motif of epsin as a cancer therapeutic-perspective in brain tumor therapy through regulating VEGFR2 signaling. Vessel Plus 1:3-11|
|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|
|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|
|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|
|Geng, Xin; Cha, Boksik; Mahamud, Md Riaj et al. (2016) Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development. Dev Biol 409:218-233|
|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|
|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|
Showing the most recent 10 out of 28 publications