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.
Highlights
Netrins are laminin-like secreted molecules that are involved in axon guidance, angiogenesis, and the formation of blood vessel networks [1,2,3,4]
The level of netrin-4 in human umbilical vein endothelial cell (HUVEC) is about 123pg/mL (Fig 1C), and it is about 72pg/mL in normal rat cornea (Fig 1C), which could not be detected 7 days after alkali-burn (Fig 1C)
Western blot results showed that netrin-4 expressed in normal rat cornea, after alkali-burn treatment there was no expression on day 1and 3
Summary
Netrins are laminin-like secreted molecules that are involved in axon guidance, angiogenesis, and the formation of blood vessel networks [1,2,3,4]. The netrin system consists of at least five ligands (netrin-1, -2, -4, -G1a, and -G1b) and six receptors (neogenin, DCC, Unc5A, -B, -C, and -D) [5]. Netrins act as bifunctional cues for angiogenesis in axonal guidance. Both netrin-1 and netrin-4 were implicated in angiogenesis [6,7,8,9,10,11], but the role of netrins in vasculature remains unclear.
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