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Therapeutic effects of topical netrin-4 inhibits corneal neovascularization in alkali-burn rats.

Han Y, Shao Y, Liu T, Qu YL, Li W, Liu Z - PLoS ONE (2015)

Bottom Line: Netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors.We found that netrin-4 functions similarly as netrin-1 in angiogenesis.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.

View Article: PubMed Central - PubMed

Affiliation: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.

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.

No MeSH data available.


Related in: MedlinePlus

Levels of netrin-4 in endothelial cells, and in cornea before and after alkali-burn were detected by ELISA, IHC and Western blot.Netrin-4 expression in normal (A) and after alkali-burn rat cornea (B) by immunohistochemical staining. Netrin-4 concentrations in rat cornea and HUVEC (C). Netrin-4 concentration in normal rat cornea and different time after alkali-burn treatment.
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pone.0122951.g001: Levels of netrin-4 in endothelial cells, and in cornea before and after alkali-burn were detected by ELISA, IHC and Western blot.Netrin-4 expression in normal (A) and after alkali-burn rat cornea (B) by immunohistochemical staining. Netrin-4 concentrations in rat cornea and HUVEC (C). Netrin-4 concentration in normal rat cornea and different time after alkali-burn treatment.

Mentions: The levels of netrin-4 in endothelial cells and cornea before and after alkali-burn were first determined by using ELISA, IHC and Western blot. The level of netrin-4 in 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). Meanwhile, we performed immunohistochemical staining and found that netrin-4 (Fig 1A) was expressed in both normal corneal epithelium and stroma. Strong staining was detected in the membrane of epithelial cells. But there wasn’t netrin-4 expression 7 days after alkali-burn (Fig 1B). Western blot results showed that netrin-4 expressed in normal rat cornea, after alkali-burn treatment there was no expression on day 1and 3. After 7days, there was weak netrin-4 expression in rat cornea. Then netrin-4 expression increased slowly at day 14 and 21(Fig 1D).


Therapeutic effects of topical netrin-4 inhibits corneal neovascularization in alkali-burn rats.

Han Y, Shao Y, Liu T, Qu YL, Li W, Liu Z - PLoS ONE (2015)

Levels of netrin-4 in endothelial cells, and in cornea before and after alkali-burn were detected by ELISA, IHC and Western blot.Netrin-4 expression in normal (A) and after alkali-burn rat cornea (B) by immunohistochemical staining. Netrin-4 concentrations in rat cornea and HUVEC (C). Netrin-4 concentration in normal rat cornea and different time after alkali-burn treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390284&req=5

pone.0122951.g001: Levels of netrin-4 in endothelial cells, and in cornea before and after alkali-burn were detected by ELISA, IHC and Western blot.Netrin-4 expression in normal (A) and after alkali-burn rat cornea (B) by immunohistochemical staining. Netrin-4 concentrations in rat cornea and HUVEC (C). Netrin-4 concentration in normal rat cornea and different time after alkali-burn treatment.
Mentions: The levels of netrin-4 in endothelial cells and cornea before and after alkali-burn were first determined by using ELISA, IHC and Western blot. The level of netrin-4 in 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). Meanwhile, we performed immunohistochemical staining and found that netrin-4 (Fig 1A) was expressed in both normal corneal epithelium and stroma. Strong staining was detected in the membrane of epithelial cells. But there wasn’t netrin-4 expression 7 days after alkali-burn (Fig 1B). Western blot results showed that netrin-4 expressed in normal rat cornea, after alkali-burn treatment there was no expression on day 1and 3. After 7days, there was weak netrin-4 expression in rat cornea. Then netrin-4 expression increased slowly at day 14 and 21(Fig 1D).

Bottom Line: Netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors.We found that netrin-4 functions similarly as netrin-1 in angiogenesis.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.

View Article: PubMed Central - PubMed

Affiliation: Eye Institute of Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.

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.

No MeSH data available.


Related in: MedlinePlus