title: Therapeutic effects of topical netrin-4 inhibits corneal neovascularization in alkali-burn rats.
abstract: Netrins are secreted molecules involved in axon guidance and angiogenesis. However, the role of netrins in the vasculature remains unclear. Netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors. Previously, we found that netrin-1 acts as an anti-angiogenic factor in rats by inhibiting alkali burn-induced corneal neovascularization. Here, we further investigate the effects of netrin-4, another member of the same netrin family, on neovascularization in vitro and in vivo. We found that netrin-4 functions similarly as netrin-1 in angiogenesis. In vitro angiogenesis assay shows that netrin-4 affected human umbilical vein endothelial cell (HUVEC) tube formation, viability and proliferation, apoptosis, migration, and invasion in a dose-dependent manner. Netrin-4 was topically applied in vivo to alkali-burned rat corneas on day 0 (immediately after injury) and/or day 10 post-injury. Netrin-4 subsequently suppressed and reversed corneal neovascularization. Netrin-4 inhibited corneal epithelial and stromal cell apoptosis, inhibited vascular endothelial growth factor (VEGF), but promoted pigment epithelium-derived factor (PEDF) expression, decreased NK-KB p65 expression, and inhibits neutrophil and macrophage infiltration. These results indicate that netrin-4 shed new light on its potential roles in treatmenting for angiogenic diseases that affect the ocular surface, as well as other tissues.
authors: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Yun
authors: Y
authors: Han
authors: Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors: Yi
authors: Y
authors: Shao
authors: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Tingting
authors: T
authors: Liu
authors: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Yang-Luowa
authors: YL
authors: Qu
authors: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Wei
authors: W
authors: Li
authors: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Zuguo
authors: Z
authors: Liu
mesh_terms: D000287:Administration, Topical; D000468:Alkalies / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003315:Cornea / Q000187:drug effects* / Q000473:pathology; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D005126:Eye Burns / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000235:genetics; D000075388:Netrin-1; D000075385:Netrins; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000468:Alkalies; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; C416214:Ntn4 protein, mouse; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1