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Hyoung Jo, Kyung A Kim, Sang Hoon Jung, Sang In Park, Hye Bin Yim, Su A Kim, Kui Dong Kang; Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5385.
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Sulodexide is a mixed glycosaminoglycan which consists of a mixture of heparin and dermatan sulfate (DS). It has been used for proteinuria and vascular pathologies associated to diabetes. The aim of this study is to investigate whether sulodexide is effective in inhibiting retinal neovascularization in an oxygen induced retinopathy (OIR) mouse model.
ICR neonatal mice were exposed to 75% oxygen from postnatal day (P)7 until P12 and returned to room air (21% oxygen) for five days (P12 to P17). Mice were subjected to daily intraperitoneal injection of sulodexide (5 mg/kg, 15 mg/kg) and saline from P12 to P17. Bevacizumab (100µg/4 µl) was injected intravitreally at P12 and served for positive control. Retro-orbital injection of FITC-dextran was performed and retinal flat mounts were viewed by fluorescence microscopy and photographed. The nonperfused area was quantified from the digital images in a masked fashion using image analysis software (NIH ImageJ). Immunohistochemistry and Western blot analysis were used to characterize the angiogenic processes involved in OIR and to demonstrate the anti-angiogenic activity of sulodexide in vivo. Tube formation assay and cell migration assay of human umbilical vein endothelial cells (HUVECs) were performed to evaluate the anti-angiogenic activity of sulodexide in vitro.
The retina of the OIR induced mouse (P17) had a distinctive area of central nonperfusion. In the retina of sulodexide-injected mouse (15mg/kg), this central ischemic area was significantly decreased (2.5±0.6mm2 vs 1.3±0.5 mm2, P<0.05). The mean numbers of neovascular nuclei counted in OIR induced mouse (P17) and sulodexide-injected mouse (15 mg/kg) were significantly different in HE staining. Hyperbaric oxygen exposure resulted in an increase of VEGF, MMP-2, MMP-9 and when mice were treated with sulodexide, a dose dependent reduction in VEGF, MMP-2, MMP-9 was observed. In addition, sulodexide significantly inhibited tube formation and cell migration of HUVECs in vitro and did not show cytotoxicity in a concentration from 1-100 μg/ml.
Our study demonstrates the anti-angiogenic effect of sulodexide in a mouse model of OIR in vivo. These results suggest that sulodexide can be one of the candidate supplementary substances to be used for the treatment of various ocular vascular pathologies such as AMD or diabetic retinopathy.
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