Zhongxiao Wang1, Rui Cheng1, Kyungwon Lee1, Puneet Tyagi1, Lexi Ding1, Uday B Kompella1, Jing Chen1, Xun Xu2, Jian-Xing Ma2. 1. From the Department of Ophthalmology, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China (Z.W., X.X.); Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City (Z.W., R.C., K.L., L.D., J.-x.M.); Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora (P.T., U.B.K.); Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China (L.D.); and Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (J.C.). 2. From the Department of Ophthalmology, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China (Z.W., X.X.); Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City (Z.W., R.C., K.L., L.D., J.-x.M.); Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora (P.T., U.B.K.); Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China (L.D.); and Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (J.C.). jian-xing-ma@ouhsc.edu drxuxun@sjtu.edu.cn.
Abstract
OBJECTIVE: The deficiency of very low-density lipoprotein receptor resulted in Wnt signaling activation and neovascularization in the retina. The present study sought to determine whether the very low-density lipoprotein receptor extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. APPROACH AND RESULTS: A plasmid expressing the soluble VLN was encapsulated with poly(lactide-co-glycolide acid) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain nanoparticle were used as negative control. MTT, modified Boyden chamber, and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell proliferation, migration, and tube formation. Vldlr(-/-) mice, oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models were used to evaluate the effect of VLN-NP on ocular neovascularization. Wnt reporter mice (BAT-gal), Western blotting, and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced endothelial cell proliferation, migration, and tube formation. Intravitreal injection of VLN-NP inhibited abnormal neovascularization in Vldlr(-/-), oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models, compared with low-density lipoprotein receptor extracellular domain nanoparticle. VLN-NP significantly inhibited the phosphorylation of low-density lipoprotein receptor-related protein 6, the accumulation of β-catenin, and the expression of vascular endothelial growth factor in vivo and in vitro. CONCLUSIONS: Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has antiangiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathological ocular angiogenesis and potentially other vascular diseases affected by Wnt signaling.
OBJECTIVE: The deficiency of very low-density lipoprotein receptor resulted in Wnt signaling activation and neovascularization in the retina. The present study sought to determine whether the very low-density lipoprotein receptor extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. APPROACH AND RESULTS: A plasmid expressing the soluble VLN was encapsulated with poly(lactide-co-glycolide acid) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain nanoparticle were used as negative control. MTT, modified Boyden chamber, and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell proliferation, migration, and tube formation. Vldlr(-/-) mice, oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models were used to evaluate the effect of VLN-NP on ocular neovascularization. Wnt reporter mice (BAT-gal), Western blotting, and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced endothelial cell proliferation, migration, and tube formation. Intravitreal injection of VLN-NP inhibited abnormal neovascularization in Vldlr(-/-), oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models, compared with low-density lipoprotein receptor extracellular domain nanoparticle. VLN-NP significantly inhibited the phosphorylation of low-density lipoprotein receptor-related protein 6, the accumulation of β-catenin, and the expression of vascular endothelial growth factor in vivo and in vitro. CONCLUSIONS: Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has antiangiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathological ocular angiogenesis and potentially other vascular diseases affected by Wnt signaling.
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